CN1367688A - Compositions containing immunotoxins and agents that inhibit dendritic cell maturation for inducing immune tolerance to graft - Google Patents

Compositions containing immunotoxins and agents that inhibit dendritic cell maturation for inducing immune tolerance to graft Download PDF

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CN1367688A
CN1367688A CN00808770A CN00808770A CN1367688A CN 1367688 A CN1367688 A CN 1367688A CN 00808770 A CN00808770 A CN 00808770A CN 00808770 A CN00808770 A CN 00808770A CN 1367688 A CN1367688 A CN 1367688A
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dendritic cell
factor
cell maturation
immunotoxin
receptor
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D·M·内维勒
J·M·托马斯
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United States, Represented by Secretary Department of Health
US Department of Health and Human Services
UAB Research Foundation
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UAB Research Foundation
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/0004—Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/515—Animal cells
    • A61K2039/5154—Antigen presenting cells [APCs], e.g. dendritic cells or macrophages

Abstract

The present invention provides a method of inducing immune tolerance to a graft in a recipient, comprising administering to the recipient an immunotoxin, thereby reducing the recipient's T-cell population; and administering to the recipient an agent that inhibits dendritic cell maturation. The present invention also provides a method of screening for an agent that acts synergistically with an immunotoxin in inducing immune tolerance and a method of screening for an agent that inhibits dendritic cell maturation. The present invention also provides a method of treating a subject with an autoimmune disease, comprising administering to the subject an immunotoxin, thereby reducing the subject's T-cell population; and administering to the subject an agent that inhibits dendritic cell maturation. Also provided herein is a composition comprising an immunotoxin and an agent that inhibits dendritic cell maturation.

Description

Be used to induce compositions immunologic tolerance, that comprise the factor of immunotoxin and inhibition dendritic cell maturation to graft
Background of invention
Invention field
The present invention relates to a kind of and suppress the technology that immunotoxin that the factor of dendritic cell maturation combines comes inducing immune tolerance.The invention belongs to immunobiologic field.
Background technology
For ideal is will see the xenotransplantation of finishing success and do not need indefinite duration and keep non-specificly with immunosuppressant and do not have for the patient and doctor of side effect of concomitant immunity depressant, and transplantation tolerance is still a unintelligible target.As the situation of many implantation methods, the homotransplantation that guarantees to live may be difficult.In addition, secular immunosuppressant may be debatable.
In the past 10 in the period of, with cyclosporin, azathioprine, prednisone and various other be used to the most transplant recipient of having kept the immunosuppressant immunosuppressant treatment.In the U.S., the average year expense of keeping immunosuppressant therapy is Shi $10 approximately, and 000.Except described expense, these medicaments have sizable side effect because of its nonspecific effect, and described side effect comprises function compromise and the susceptibility of increase to infecting that makes cell and organ.The main target of transplantation immunity in biology is: produce the specific immunologic tolerance of graft; Described immunologic tolerance has makes the patient break away from the potentiality that continue the side effect of pharmacology's immunosuppressant and complication of following and expense.
Aspect rodent, will resist the thymus injection of T cell therapy (antilymphocyte globulin) and donorcells to be used in combination (Posselt etc., Science 1990; 249:1293-1295 and Remuzzi etc., Lancet 1991; 337:750-752).Proved that in rodent model successful thymic tolerance relates to: before organ allograft, receptor thymus is exposed to the isoantigen of same donor from donor.Yet at the toleration of also not reporting thymus aspect the big animal, and the relation of the toleration of it and philtrum is unknown.
A kind of method that realizes immunologic tolerance is: before transplanting, owing to wish to induce toleration to the graft of back, and make receptor be exposed to cell from donor.This method relates to: after having used antilymphocyte serum (ALS) soon or radiation after in soon the thymus of described receptor, place and present the antigenic donorcells of MHC I class (for example bone marrow).But this method has proved and has been difficult to be suitable for the primates (for example monkey or people) that lives.ALS and/or radiation make the host to disease or side effect sensitivity, and/or ALS and/or radiation are effective inadequately.
If can have induce for transplant, particularly for the safety method of heteroplastic specific immune tolerance; So, owing to it can be applied to new transplanting immediately, and because it can be applied to existing graft in the stable receptor of graft function potentially, this method will have very big value, and can cause whole world patient and be engaged in the attention of transplanting the doctor.Therefore, the immunologic tolerance that expects to have a kind of high specific is induced.In addition, need a kind of method that in primates, is used to give toleration and does not have use ALS or radiating ill-effect.And described target is acquired tolerance rather than postpones rejection simply.An important purpose is: described rejection is suppressed to repulsion does not become a kind of degree that reduces the factor of transplant recipient average life.
Summary of the invention
The invention provides a kind of method of inducing the immunologic tolerance of graft in the receptor, described method comprises: give this receptor a kind of immunotoxin, reduce the T cell mass of this receptor thus; And give this receptor a kind of factor that suppresses dendritic cell maturation.Give this receptor the factor of described inhibition dendritic cell maturation at least once, and preferably gave the same day in transplanting.More preferably be during the course of treatment in one to two week after the transplanting, to give this receptor again four to 14 times with the factor of described inhibition dendritic cell maturation.Can be arbitrarily selectively, can be before transplanting give this receptor, and/or can be before the described graft of gathering with the factor of described inhibition dendritic cell maturation, give this donor with the factor of described inhibition dendritic cell maturation.The factor of described inhibition dendritic cell maturation can be a kind of inhibitor of Nf κ B nuclear translocation, and described nuclear translocation inhibitor comprises: for example, and the derivant or the analog of deoxyspergualin, methyl-deoxyspergualin and other deoxyspergualin.The factor of other inhibition dendritic cell maturation can comprise: for example, and a kind of soluble il-17 (IL-17) receptor Fc fusion rotein, a kind of glucocorticoid, the bonded a kind of blocker of tumor necrosis factor, the bonded a kind of blocker of granulocyte macrophage colony stimulating factor, the bonded a kind of blocker of IL-12p70 or the bonded a kind of blocker of IL-1 β.The factor that suppresses dendritic cell maturation also can comprise: a kind of a kind of blocker of immaturity dendritic cell epi-position or a kind of a kind of blocker that relates to the dendritic cell precursor epi-position of dendritic cell maturation, described dendritic cell precursor epi-position is for example: a kind of anti-CD40 part (promptly anti-CD154), and this anti-CD40 part a kind of derivant that can be 5C8 or its analog more specifically.
The present invention also provides a kind of screening technique, and promptly screening and a kind of immunotoxin play the method for the synergistic factor aspect inducing immune tolerance; Described method comprises: a kind of donor graft is transplanted in the receptor, is given this receptor a kind of immunotoxin, reduce the T cell mass of this receptor thus; Give this receptor the described factor to be screened; Obtain a sample that comprises dendritic cell; And be determined in this sample and express or can be by the percent of the dendritic cell of one of abduction delivering mature dendritic cell species specificity labelling; Wherein low percent shows synergism.Equally, the invention provides a kind of screening technique, i.e. screening suppresses the method for the factor of dendritic cell maturation, and this method comprises: obtain an immaturity dendritic cell group by portion from a sample curee, that comprise dendritic cell; Cultivate described cell mass existing under the described situation of waiting to screen the factor; And mensuration is expressed or can be by the percent of the dendritic cell of one of abduction delivering mature dendritic cell species specificity labelling; Wherein low percent shows the inhibition to dendritic cell maturation.The present invention also provides a kind of Therapeutic Method, i.e. treatment suffers from a kind of curee's of autoimmune disease method; Described method comprises: give this curee a kind of immunotoxin, reduce this curee's T cell mass thus; And give this curee with a kind of factor that suppresses dendritic cell maturation.
In this article, also provide a kind of compositions, described compositions comprises a kind of immunotoxin and a kind of factor that suppresses dendritic cell maturation.More particularly, the invention provides a kind of compositions, wherein, described immunotoxin is a kind of anti-T cellular immunization toxin at the CD3 epi-position, and perhaps therein, the factor of described inhibition dendritic cell maturation is a kind of inhibitor of Nf κ B nuclear translocation.
The accompanying drawing summary
Fig. 1 shows: by with DSG described transplant recipient being carried out therapeutic alliance with immunotoxin and at 0-14 days the 0th day and the+1 day, induce the renal transplantation toleration, caused being mainly the polarization of Th2 cytokine.During second week after transplanting, in the group of accepting described therapeutic alliance, demonstrate IL4 polarization (with only to compare the level of IL4 with the group of immunotoxin treatment lower, and compare the level of IL4 with the interferon gamma level lower).When 4 weeks, the group that the described DSG of acceptance reached for two weeks is demonstrating a kind of increase lasting, gradually aspect the IL4 polarization; And in accepting the group that DSG only reaches 5 days, described polarization is then no longer lasting, and the cytokine pattern is opposite.The type of polar appearance of described IL4 and anti-CD 3 immunotoxins is irrelevant, and described anti-CD 3 immunotoxins is complete IgG form or F (Ab) 2Form.
Fig. 2 A, 2B, and 2C shown to or with complete IgG immunotoxin (FN18-CRM9) or with F (Ab) 2Immunotoxin (FNl8-F (Ab) 2-CRM9) or with the Rhesus Macacus peripheral blood lymphocyte of the firm acquisition of buffered saline (PBS) contrast treatment carry out the result that RT-PCR analyzes.Fig. 2 A is illustrated in IL-2, the IL-4 under the situation that does not have DSG, the mRNA of IL-10, IFN-γ.Fig. 2 B has represented IL-2, the IL-4 in the cell for the treatment of with DSG (2.5 μ g/ml), the mRNA of IL-10, IFN-γ.Fig. 2 C has represented the density ratio that various mRNA and actin contrast.
Detailed Description Of The Invention
The invention provides a kind of Short-course therapy side that utilizes a kind of immunotoxin inducing immune tolerance Case when described immunotoxin is united use with the factor that suppresses dendritic cell maturation, is then being protected When holding graft function, prevent graft rejection. Therefore, the invention provides a kind of in acceptor Induce the method to the immunological tolerance of graft, described method comprises: give that this receptor is a kind of exempts from The epidemic disease toxin reduces the T cell mass of this receptor thus; And it is thin to give a kind of inhibition dendron of this receptor The factor of born of the same parents' maturation.
As used everywhere, " graft " can comprise homologous organs or xenogenesis organ, group Knit or the graft of cell. For example, this graft can be selected from kidney, liver, heart, pancreas, The stem cell precursor of lung, skin graft and pancreas islet, liver cell, stem cell precursor and differentiation The cellular transplant of separation.
As used everywhere, described " acceptor " or " curee " are preferably mammal, More preferably, described mammalian receptors is a kind of primate, and further more preferably is the people. Quilt Described " acceptor " or " curee " for the treatment of comprises single people, the animal of raising and train, domestic animal (for example ox, horse, pig, etc.) and pet (for example cat and dog).
As used everywhere, " donor " can be corpse or donor alive.And this donor can be same species with the curee who is treated, and perhaps, can be different species with the curee who is treated.Therefore, use method of the present invention, can carry out cross transplantation (being xenogeneic transplanting or xenotransplantation) and the interior transplanting (being transplanting or homotransplantation of the same race) of same primates pedigree between the primates kind.Under the situation that has this immunologic tolerance induction scheme, connect extremely sensitive xenotransplantation and can both keep function.
The donor graft that is used for the inventive method can comprise: for example pass through described donor or the genetic engineering modified and altered cell of donorcells.For example, can described donorcells is engineered, to reduce antigenicity or to reduce the sensitivity (R.Weiss, Nature 391:327-28 (1998)) of institute's transplanted cells to the immunity infringement.
As used everywhere, " factor that suppresses dendritic cell maturation " refers to: when contacting with dendritic cell precursor, thereby suppress any factor that all or part of precursor makes its labelling that can not express mature dendritic cell.Therefore, compare with the cell number of presentation markup under the situation of the factor that does not have described inhibition dendritic cell maturation, the factor that suppresses dendritic cell maturation can cause the cell of presentation markup approximately to reduce 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%, and described labelling is film CD83, DR or CD86 or nuclear Rel-B for example.Therefore, as what more fully describe in embodiment provided herein, the effectiveness of the inhibitor of dendritic cell maturation is estimated in reducing of percent that can be by measuring the cell of expressing the mature dendritic cell labelling.
The factor of described inhibition dendritic cell maturation can be a kind of inhibitor of Nf κ B nuclear translocation.More particularly, this kind nuclear translocation inhibitor of Nf κ B can be deoxyspergualin or derivatives thereof or analog, described derivant or analog comprise: for example, methyl-deoxyspergualin or a kind of analog that does not have a deoxyspergualin of chiral centre are (for example: LF08-0299) (Andoins etc., 1996, by reference the document is attached to herein).Can use other derivant or the analog of deoxyspergualin, described other derivant or analog comprise: for example 4,518, No. 532 United States Patent (USP)s, 4,518, No. 532 United States Patent (USP)s, 4,525, No. 299 United States Patent (USP)s, 4,956, No. 504 United States Patent (USP)s, 5,162, No. 581 United States Patent (USP)s, 5,476, those derivants or the analog identified among No. 870 United States Patent (USP)s, 5,637, No. 613 United States Patent (USP)s, W.O.96/24579, EP600762, EP669316, EP7433000, EP765866 and the EP755380; By reference these documents are attached to herein.
Preferably, the factor of described inhibition dendritic cell maturation activate one or more Th2 cytokines that plant to rely on NF-AT (for example, one or more kinds be selected from by IL2, IL4, and the cytokine of the group formed of IL10).And the factor of described inhibition dendritic cell maturation (for example: interferon gamma) preferably suppresses one or more Th1 cytokines of planting dependence Nf κ B.Such activation or to suppress may be respectively because the increase minimizing of described cytokine gene expression causes.Therefore, handle the change of the mRNA level of the described cytokine of can encoding or the change of protein level with the described factor.In one embodiment of the invention, the described factor activates one or more and plants the Th2 cytokine that relies on NF-AT, and suppresses one or more and plant the Th1 cytokine that relies on Nf κ B.Therefore, for example described factor can activate IL4 and suppress IFN-.
On the other hand, the factor of described inhibition dendritic cell maturation can be: a kind of soluble il-17 (IL-17) receptor Fc fusion rotein, a kind of glucocorticoid, the bonded a kind of blocker of tumor necrosis factor (TNF-α), the bonded a kind of blocker of granulocyte macrophage colony stimulating factor (GM-CSF), the bonded a kind of blocker of IL-12p70 or the bonded a kind of blocker of IL-1 β.The factor that suppresses dendritic cell maturation also can comprise: a kind of blocker of the epi-position of a kind of a kind of blocker of epi-position of immaturity dendritic cell or a kind of dendritic cell precursor that relates to dendritic cell maturation, the epi-position of described dendritic cell precursor is for example: a kind of anti-CD40 part (promptly anti-CD154), more particularly, this anti-CD40 part a kind of derivant that can be 5C8 or its analog.Those skilled in the art will appreciate that: can use the factor of described inhibition dendritic cell maturation to produce synergism or additive effect in the mode of associating.
Preferably, give this receptor the factor of described inhibition dendritic cell maturation at least once.More preferably, can be at least transplanting in the same day and first week after transplanting other 1 day, 2 days, 3 days, 4 days, 5 days, 6 days or 7 days, perhaps other 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days in initial two weeks after transplanting the same day, 11 days, 12 days, 13 days or 14 days, give this receptor with the factor of described inhibition dendritic cell maturation.Can be arbitrarily selectively, this can be given to optimize the course of treatment, thereby transcribe aspect the activation of cytokine of approach mediation at NF-AT and/or transcribe at Nf κ B aspect the inhibition of cytokine of approach mediation, produce the increase that continues.Therefore, in one embodiment,, give the described factor every day transplanting the same day and other 13 or 14 times.
Except after transplanting the same day and transplanting the same day, giving the described factor, can be before transplanting additionally give this receptor with the factor of described inhibition dendritic cell maturation.For example, can be between preceding 24 hours and 0.25 hour of transplanting, and preferably, give this receptor deoxyspergualin at least once transplanting preceding 23 hours, 22 hours, 21 hours, 20 hours, 19 hours, 18 hours, 17 hours, 16 hours, 15 hours, 14 hours, 13 hours, 12 hours, 11 hours, 10 hours, 9 hours, 8 hours, 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, 0.5 hour.Can be arbitrarily selectively, the present invention can further comprise: before the graft of gathering, the factor that suppresses dendritic cell maturation is given the donor of this graft.For example, can be before the graft of gathering between 24 hours and 0.25 hour, and preferably before the graft of gathering 23 hours, 22 hours, 21 hours, 20 hours, 19 hours, 18 hours, 17 hours, 16 hours, 15 hours, 14 hours, 13 hours, 12 hours, 11 hours, 10 hours, 9 hours, 8 hours, 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, 0.5 hour, give this donor deoxyspergualin at least once.Though giving the time course of the inhibitor of dendritic cell maturation before transplanting may be restricted owing to the Unpredictability of organ acquisition and organ availability; But preferably before transplanting, give this receptor, and/or before this graft of gathering, give this donor described inhibitor with described inhibitor.
The preferred dose of the inhibitor of described dendritic cell maturation also will change according to following situation, described following situation promptly: the species of used concrete inhibitor, described receptor, age, body weight and general health situation, administering mode, or the like.Therefore, the dosage of specify precise is impossible or unessential, because present technique field those of ordinary skill can not determined suitable time course by undue test.As an example, the dosage of described deoxyspergualin can be between 0.1 mg/kg/d and 10 mg/kg/d, comprise 0.5,1.0,1.5,2.0,2.5,3.0,3.5,4.0,4.5,5.0,5.5,6.0,6.5,7.0,7.5,8.0,8.5,9.0,10.0mg/kg/d or any amount between it.
As used everywhere, " immunotoxin " can be a kind of immunotoxin at T cell described CD3 epi-position, anti-.This immunotoxin can be a kind of immunoconjugates or fusion rotein.This immunotoxin or can be monovalent perhaps can be a bivalence.The anti-T cellular immunization toxin of described pair of valency can be UCHT1-CRM9 or derivatives thereof or analog.The immunotoxin of the anti-T cell of described bivalence can comprise a toxin moiety and at an orientation (targeting) part of T cell CD3 ε epi-position, and this toxin moiety can be a diphtheria toxin, diphtherotoxin.The bivalence fusion immunotoxin that the anti-T cellular immunization toxin of described bivalence can be a kind of through engineering approaches.In U.S.'s serial number 09/064,413 and PCT/US98/04303, various immunotoxins and therapeutic scheme have been described more fully; By reference described document is attached to herein.For example, this immunotoxin can be a kind of complete IgG immunotoxin (for example FN18-CRM9), perhaps can be a kind of F (Ab) of described immunotoxin 2Form (FN18-F (Ab) for example 2CRM9).
In the present invention, give twice to the described immunotoxin of major general, and preferably give described immunotoxin transplanting the same day and after transplanting second day at least.Can begin to give described immunotoxin in preceding 72 hours to 0 hour in transplanting, and reach a couple of days after this continuing to give immunotoxin.Preferably, can be before xenotransplantation 72-48 hour and the 24-0 before homotransplantation hour, described immunotoxin be given this receptor, gives this donor or gives its both.Preferably after transplanting, give this receptor with described immunotoxin and reach one day, two days or three days or any time between it.Considered immunotoxin give can be carried out four, five, six or seven days always, but like this time-histories that gives immunotoxin of time expand may need to solve the problem that t antibody produces; The generation of described t antibody approximately starts from giving after 5 days of immunotoxin.Can whenever beginning after transplanting, give the curee with described immunotoxin.Therefore, considered before not accept immunotoxin curee treatment, that have the long-term surviving graft and still can be benefited, avoided thus carry out the needs of long-term treatment with immunosuppressant owing to giving immunotoxin.Further considered: beginning to demonstrate the graft receptor that repels sign can be benefited owing to giving immunotoxin, thereby reduces or eliminates this repulsive interaction.Even in the receptor of formerly having treated with immunotoxin, can further treat the receptor that demonstrates rejection therefore, by means of giving extra immunotoxin.
As used everywhere, the T cell that described immunotoxin preferably reduces in the described curee's or receptor blood and the lymph node momently reaches at least one log unit.Preferably will reduce the T cell number in described blood and the lymph node momently 0.7,0.8,0.9,1,1.1,1.2,1.3,1.4,1.5,1.6,1.7,1.8,1.9,2 or 3 log unit, perhaps reduce the amount in any interval between 0.7 log unit and 3 log units momently.So-called " reducing momently " means: before the T cell begins to return to normal level, reduce the T cell of 0.7 log unit to 3 log unit at least 4 days in blood and lymph part.
This method can comprise further and gives this receptor with a kind of immunosuppressant thing.As used everywhere, a kind of immunosuppressant thing or immunosuppressant comprise: for example, and methylprednisolone, Neoral, cyclosporin, Mycophenolic Acid moefitil, tacrolimus, azathioprine, rapamycin (rapamycin), a kind of steroid or its any combination.Can be before transplanting 24 hours to 0 hour, begin to give described immunosuppressant thing, and last till two weeks after this always.Can give preferably that described immunosuppressant thing reached 4,5,6,7,8,9,10,11,12,13,14 days at least or the time in any interval.The scheme of the immunotoxin of described associating and the inhibitor of dendritic cell maturation allows the immunosuppressant therapy of short-term, and excludes carry out the needs of long-term treatment with immunosuppressant; Avoid being accompanied by the side effect that permanent immunity suppresses thus.Thereby when employing and immunotoxin with suppress immunosuppressant that the factor of dendritic cell maturation combines during the course of treatment, this immunosuppressant course of treatment is compared with the therapy that is used for preventing transplant rejection traditionally, what the persistent period may be short, and/or dosage is lower.
In the inventive method of inducing immune tolerance and treatment immunological diseases, can use complementary therapy simultaneously.Therefore, the present invention includes at least a method with immunotoxin (IT) inducing immune tolerance: (1) gives and inducing tolerance by IT is united with one or more factors that suppress dendritic cell maturation; (2) by give IT, one or more plant to suppress the factor of dendritic cell maturations and the combination of at least a immunosuppressant or a kind of immunosuppressant, and inducing tolerance.Can be before giving immunotoxin, simultaneously or implement this complementary therapy afterwards.As what be further described below, can or give the different time of immunotoxin or simultaneously, described receptor be implemented different complementary therapies in the transplanting incident.
Because can be with immunotoxin with suppress to give immunosuppressant before the factor in treatment of dendritic cell maturation, so, combined immunization toxin and this method that suppresses the factor of dendritic cell maturation can be used for just implementing the transplant recipient of immunosuppressant scheme.This provides significant, as to reduce or get rid of the harmful side effect of traditional immunosuppressant agent therapy and a large amount of records thereof a chance.Equally, aspect corpse transplanting and xenotransplantation, before transplanting,, may be useful especially with the factor that suppresses dendritic cell maturation and/or the processing of immunosuppressant.Under so a kind of background of transplanting pre-treatment, postponing till of immunotoxin can be transplanted back 7 days or more days.
For the patient who accepts organ transplantation, the example of timetable that gives immunotoxin and a kind of factor that suppresses dendritic cell maturation is as follows: the-24 days to 0 hour: (can be any with the factor in treatment receptor that suppresses dendritic cell maturation
Select) the 0th day: transplant, after transplanting, give primary immunity immediately
Toxin dose, and control with the factor that suppresses dendritic cell maturation
Treated this receptor first day: with the factor in treatment this receptor that suppresses dendritic cell maturation second day: give secondary immunotoxin dosage, and with the inhibition dendron
The factor in treatment this receptor of cell maturation the 3rd day: the factor in treatment this receptor of usefulness inhibition dendritic cell maturation the 6th day: with the factor in treatment this receptor that suppresses dendritic cell maturation
Perhaps the-24 days to 0 hour: (can be any with the factor in treatment receptor that suppresses dendritic cell maturation
Select) the 0th day: transplant, after transplanting, give primary immunity immediately
Toxin dose, and control with the factor that suppresses dendritic cell maturation
Treated this receptor second day: give secondary immunotoxin dosage the 4th day: with the factor in treatment acceptor control that suppresses dendritic cell maturation seven days: with the factor in treatment acceptor control that suppresses dendritic cell maturation ten days: with the factor in treatment acceptor control that suppresses dendritic cell maturation 13 days: with the factor in treatment receptor that suppresses dendritic cell maturation.
In any example, can be before this graft of gathering 24 hours to 0 hour, with this donor of factor in treatment of described inhibition dendritic cell maturation; And/or can be before transplanting, after transplanting the same day or transplanting, with the described receptor of immunosuppressant treatment.Those skilled in the art can be known along with the difference of each receptor and rely on following situation that described time course is made amendment, described following situation is promptly: the species of described receptor, age, body weight and general health situation, used specificity factor, administering mode, or the like.Therefore, it is impossible or unessential specifying a kind of definite time course.In any case those skilled in the art can determine a kind of suitable time course.
At present preferred immunotoxin dosage is: be enough to reduce 80% the dosage that the periphery blood T cell level reaches level before the injection, and be preferably and be enough to reduce 90% the dosage (perhaps especially preferred 95% or higher) that the periphery blood T cell level reaches level before the injection.For the people, this dosage should need the level of mg/kg, be similar to be used for monkey dosage level (for example: every kg body weight 0.05mg to 0.3mg); Toxicity research shows: this dosage should be stood well by the people.Therefore, can give this immunotoxin, thereby reduce the T cell mass of described receptor safely.
Can estimate the effectiveness of the described method of inducing tolerance with the well-known method in present technique field.Can evaluate the clinical manifestation of graft function and transplant rejection.For example, with a kind of method of inducing to the toleration of pancreatic cell graft or islet cell transplantation thing, can measure the level of blood-glucose, and after the immunologic tolerance induction scheme finishes, non-empty stomach blood glucose levels is remained on below the 160mg/dl, and then showing does not have transplant rejection.Other performance of transplant rejection comprises histologic characteristics's (for example: about the biopsy of graft), and for example interstitial fibrosis, the interstitial proliferation of described histologic characteristics, the small artery stenosis is narrow and the ischemic of transplant organ infringement.In addition, histology's performance of renal transplantation thing repulsion comprises duplicating and thickening of glomerular basement membrane.The clinical manifestation of repelling comprises little by little carrying out property graft malfunction.For example, in a curee's body with renal transplantation thing, the blood creatinine levels of increase will show repulsion.Normal serum creatinine level is lower than 2.0mg/dl, and more typically is about 0.5-1.5mg/dl.Increase about twice and show renal transplantation thing malfunction by the kreatinin baseline values.The raising of the existence of anti-donor antibody and anti-donor antibody level also may show the graft function obstacle.Those skilled in the art can be recognized other histological indices and the clinical indices of repulsion.
The present invention also provides a kind of screening technique, and promptly screening and a kind of immunotoxin play the method for the synergistic factor aspect inducing immune tolerance; Described method comprises: a kind of donor graft is transplanted in the receptor, is given this receptor a kind of immunotoxin, reduce the T cell mass of this receptor thus; Give this receptor the described factor to be screened; Obtain a sample that comprises dendritic cell; And be determined in this sample and express or can be by the percent of the dendritic cell of abduction delivering mature dendritic cell specific marker; Wherein low percent shows synergism.As used everywhere, " sample that comprises dendritic cell " can comprise: for example, and lymph node biopsy tissue, blood sample or tonsil biopsy.Equally, as used everywhere, " specific marker of mature dendritic cell " can comprise: for example, and film CD83, film DR, film CD86, kytoplasm P55 or nuclear Rel-B.Can detect these labellings routinely with methods known in the art.(O ' Doherty etc., 1997).
Equally, the invention provides a kind of screening technique, i.e. screening suppresses the method for the factor of dendritic cell maturation, and this method comprises: by portion immature dendritic cell group of sample acquisition who comprises dendritic cell from an experimenter; Existing described waiting to screen under the situation of the factor, cultivate this cell mass; And mensuration is expressed or can be by the percent of the dendritic cell of abduction delivering mature dendritic cell specific marker; Wherein low percent shows the inhibition to dendritic cell maturation.Be preferably in the MNC-CM that is supplemented with TNF α, cultivate this cell mass.
The present invention also provides a kind of Therapeutic Method, i.e. treatment suffers from a kind of curee's of autoimmune disease method; Described method comprises: give this curee a kind of immunotoxin, reduce this curee's T cell mass thus; And give this curee with a kind of factor that suppresses dendritic cell maturation.Can comprise with the autoimmune disease of this method treatment: for example, systemic lupus erythematosus (sle), myasthenia gravis, stiff man syndrome, autoimmune thyroid disease, chorea minor, rheumatoid arthritis.Those skilled in the art will appreciate that the various modes of estimating described treatment effectiveness; For example, the alleviating of clinical symptoms (muscle function that for example reduce pain, improved, the thyroid function of having improved) and the T cell that has reduced or the histology's evidence or the biochemistry evidence of mature dendritic cell.
In this method of treatment autoimmune disease, preferably during about two weeks, give this curee at least once with the factor of described inhibition dendritic cell maturation, perhaps give twice, three times, four times, five times, six times, seven times, eight times, nine times, ten times, ten once, ten secondaries, 13 times or 14 times; And be preferably in be less than five days during in, preferably give described immunotoxin at least once, twice or three times.Discussed in the text as inducing immune tolerance in the above,, then can give immunotoxin and reach about 4 days if solved the problem that described t antibody produces.On the other hand, described Therapeutic Method can further comprise and gives this curee with a kind of immunosuppressant.But, to compare with the immunosuppressant agent therapy that uses traditionally, the therapy limited duration and the dosage of described immunosuppressant are lower.
Because in primate species, the immunologic function of the acceptance of control graft and repulsion and control autoimmune disease is similar; So, expect the use in conjunction of immunotoxin described herein and the factor that suppresses dendritic cell maturation successfully inducing immune tolerance or treatment autoimmune disease in human body.
The present invention also provides a kind of compositions, and described compositions comprises a kind of immunotoxin and a kind of factor that suppresses dendritic cell maturation.More particularly, the invention provides a kind of compositions, wherein, described immunotoxin is a kind of anti-T cellular immunization toxin at the CD3 epi-position; The factor of perhaps wherein said inhibition dendritic cell maturation is a kind of inhibitor of Nf κ B nuclear translocation.The factor of preferably described inhibition dendritic cell maturation activates one or more and plants the Th2 cytokine that relies on NF-AT.And the factor of described inhibition dendritic cell maturation preferably suppresses one or more and plants the Th1 cytokine that relies on Nf κ B.In one embodiment of the invention, the described factor activates the Th1 cytokine that one or more are planted the Th2 cytokine that relies on NF-AT and suppress one or more kind dependence Nf κ B.Therefore, for example described factor can activate IL4 and suppress interferon gamma.
Compositions of the present invention can further comprise a kind of pharmaceutically acceptable carrier.So-called " pharmaceutically acceptable carrier " means: be not biologically or at the undesirable material of others; That is: can and suppress that the factor one of dendritic cell maturation is genuine to give the curee with this material and described immunotoxin, and do not cause any significant undesirable biological effect, or not with deleterious mode and any component interaction that comprises the described Pharmaceutical composition of this material.Certainly can select described carrier, thereby the degraded of any effective ingredient is reduced to minimum, and any harmful side effect in described curee's body is reduced to minimum.Suitable carriers can comprise: for example, and the mixture of any material in water, pyrogen-free saline, pharmaceutically acceptable oil or these materials.This carrier also can comprise other suitable medical additive, and described additive is buffer agent, antiseptic, flavoring agent, viscosity modifier or Osmolyte regulator, stabilizing agent or suspending agent for example.
Among the embodiment that only is intended as explanation below, described the present invention in more detail, because for those skilled in the art, many modifications and variations in the present invention will be conspicuous.
Embodiment 1 is used to induce the toleration of primates and the maturation that suppresses dendritic cell momently
In inhuman primates, transplant induced with anti-CD 3 immunotoxins the same day after, the minimizing of T cell in lymph node and the blood, pass through shor time treatment then with the inhibitor 15-deoxyspergualin of Nf κ B, and suppress replying of proinflammatory cytokine, thereby promote the stable toleration of the unmatched renal homotransplantation of NHC.This synergistic mechanism is: during the T cellular-restoring phase after immunotoxin is induced, and the maturation of blocking-up dendritic cell precursor.
Normal 3 kilograms of male Rhesus Macacus have been accepted a kind of homotransplantation of kidney, and described kidney is from the unmatched donor of a kind of incoherent MHC.Use then: in twice immunotoxin injection (100 μ g/kg/d) of the 0th day and the+2 days, be reduced to 0 methylprednisolone (MP) gradually and, treated these monkeys from 7mg/kg/d at the 0th day to the+4 days (n=5) or the 0th day deoxyspergualin (2.5mg/kg/d) to the+14 days (n=5) at the 0th day to the+3 days.Other receptor was accepted immunotoxin and only MP (n=3) or is accepted immunotoxin and MP adds Neoral (100mg/kg/d) (n=3) at 0-4 days.When 5 days, 15 days and 30 days, inguinal lymph nodes and axial lymph node are carried out biopsy, and according to the labelling that whether has mature dendritic cell in immunohistochemical detection inguinal lymph nodes and the axial lymph node; Specifically, check in inguinal lymph nodes and the axial lymph node whether film CD83, DR and CD86 and nuclear Rel-B are arranged.
Immunotoxin treatment, given in 80% the receptor that MP adds deoxyspergualin x15 days renal homotransplantation thing survival, and do not have the histology's evidence or the clinical evidence of acute or chronic rejection; Immunotoxin treatment, given in 40% the receptor that MP adds deoxyspergualin x5 days renal homotransplantation thing survival; And immunotoxin treatment, only given MP or given in 0% the receptor that MP adds Neoral renal homotransplantation thing survival.In the monkey of deoxyspergualin treatment 3 the elder of surviving has been survived＞830 days (2.3 years), and has the immunology evidence of normal renal function and specific tolerance.
Compare with the lymph node from the graft of no deoxyspergualin, the extreme that demonstrates ripe dendritic cell DC from the+5 days lymph node tissues of the receptor of deoxyspergualin treatment reduces; Promptly aspect the expression of film: for DC83,58 ± 9.9 times of decreased average; For CD86,49 ± 9.0 times of decreased average; And for DR, 81 ± 13.5 times of decreased average.Rel-B nuclear positive cell has been reduced 46 ± 7.1 times.During by the 15th day, occurred partly recovering; And during by the 30th day, DR+, CD83+ and Rel-B+ cell are in the scope of contrast.The CD86+ cell is still (reduce 7.5 ± 1.8 times) that has reduced.These results show: inhibition and the sophisticated inhibition of DCp of a kind of Nf κ B of that caused by deoxyspergualin, dependent dose.
These data show: in inhuman primates, the inhibitor deoxyspergualin of Nf κ B is blocked the maturation of dendritic cell precursor in vivo.Our supposition: in this difficult model, immunotoxin and deoxyspergualin be at the unique synergism that promotes aspect the toleration, be part since memory cell and originally the T cell reduced by immunotoxin.Say that conceptive this can produce a kind of transitional environment; In this environment, the cell of T originally of building the group again is fixed to dendritic cell needs common the stimulation to activate; And deoxyspergualin suppresses dendritic cell precursor acquisition stimulatory function altogether.Last result be the time window in 2-3 week slip by a kind of environment that is similar to the birth neonate, in " non-danger " environment, the scope of both having dwindled the T cell takes place simultaneously, reduce the maturation of dendritic cell precursor again; Help toleration therefrom.Embodiment 2
In order directly to check the maturation of dendritic cell precursor, checked the isolating Rhesus Macacus peripheral blood dendritic cells precursor in the culture medium; Described culture medium comprises the MNC-CM (MCM) that has replenished with TNF α.Before adding MCM/TNF α, (0.6-10mg/ml) is added in the culture of dendritic cell precursor with deoxyspergualin.As in embodiment 1,, estimate the expression of dendritic cell maturation labelling by flow cytometry and the immunocytochemical stain by the cell centrifugation prepared product.
The data show that these are external Rel-B dyeing from the nuclear staining to the Cytoplasm painted transformation and CD83 dyeing from the film painted transformation of Cytoplasm of dyeing; Reflect dominant immaturity dendritic cell precursor phenotype in the culture that deoxyspergualin is handled.These in vitro results are consistent with the interior result of the body of embodiment 1.
Embodiment 3
As described in the embodiment 1, carry out homotransplantation.Equally, as what in embodiment 1, describe, at the 0th day and the+1 day, perhaps with the immunotoxin of complete IgG form or with F (Ab) 2The immunotoxin of form is treated described transplant recipient.Perhaps five days after transplanting, perhaps two weeks after transplanting, some described receptor is also accepted deoxyspergualin (DSG) every day.1 week, 2 weeks or 4 weeks after transplanting, the level of the level of the Th2 cytokine IL4 of analysed for plasma and Th1 cytokine interferon gamma (IFN γ).After only treating with the immunotoxin of complete IgG, from 1 thoughtful 4 weeks, the level of IFN γ and the level of IL-4 increase gradually; And the level of IL-4 is higher than IFN γ level.When the time with the treatment associating of the treatment of the immunotoxin of complete IgG and DSG, the then level of various cytokines change.During second week after transplanting, in the group of accepting described therapeutic alliance, demonstrate tangible IL4 polarization.Specifically, compare, accept the group of therapeutic alliance and express significantly lower IL4 level with the group of only treating with immunotoxin; And compare with the interferon gamma level, express significantly lower IL4 level.When 4 weeks, the group that the described DSG of acceptance reached for two weeks is demonstrating a kind of increase lasting, gradually aspect the polarization of IL4; And in accepting the group that DSG only reaches 5 days, described polarization is then no longer lasting; And the cytokine pattern is opposite.These data show: be that the IL4 polarity effect that reaches lasting is necessary two courses of treatment in week of DSG and immunotoxin associating.The type of polar appearance of described IL4 and anti-CD 3 immunotoxins is described complete IgG form or F (Ab) 2Form is irrelevant.With described F (Ab) 2Form, then this IL4 size of replying is lower; But described polarization is actually completely, because there is not measurable interferon-.Referring to Fig. 1.
Embodiment 4
The well-known RT round pcr in present technique field is used for: with complete IgG immunotoxin (FN18-CRM9), F (Ab) 2Immunotoxin (FN18-F (Ab) 2-CRM9) or the Rhesus Macacus peripheral blood lymphocyte of the firm acquisition that stimulates with phosphate buffered saline(PBS) (PBS).In Fig. 2, shown this experimental result.FN18-CRM9 induces the expression of the cytokine gene of IL-2, IL-4, IL-10 and interferon gamma; And FN18-F (Ab) 2-CRM9 only optionally induces the expression of IL-4 and IL-10.Under the situation that has the DSG of low dosage (2.5 μ g/ml), then reduce FN18-CRM9 inducing to IL-2, IL-4, IL-10 and interferon gamma.On the contrary, with FN18-F (Ab) 2The low dosage DSG of-CRM9 associating then increases IL-4 and IL-10; This is consistent with the interior data of the body among the embodiment 3.So, when increasing IL-4 and IL-10 expression, FN18-F (Ab) 2-CRM9 unites the unique effect (consistent to the inhibitory action of NF-κ B transposition with DSG) with the expression of blocking-up interferon gamma with DSG.Therefore, different with cyclosporin or FK506, DSG keeps and promotes the activation of the NF-AT transcription factor of IL-4 and IL-10, and optionally suppresses the activated channel of the cytokine of dependence NF-κ B.
In whole the application, indicated the source of data of various publication.In order more fully to describe the technology status that the present invention relates to, by reference the disclosure of these publications all is attached among the application hereby.
Though describing the present invention aspect the detail of certain embodiments of the present invention, and do not meaning that and such details is thought limitation of the scope of the invention; Think that just they are included in the scope of appending claims.
List of references 1.Andoins etc., (1996), Transplantation 62:1543-1549.2.Posselt etc., (1990), Science 249:1293-1295.3.Remuzzi etc., (1991), Lancet 337:750-752.4.O ' Doherty etc., (1997), J.of Immunol.Meth.207:185-194.

Claims (24)

1. in receptor, induce method for one kind to the immunologic tolerance of graft; Described method comprises:
(a) give described receptor a kind of immunotoxin, reduce the T cell mass of described receptor thus; And
(b) give described receptor a kind of factor that suppresses dendritic cell maturation.
2. the process of claim 1 wherein that described graft is selected from the isolated cells graft of the stem cell precursor of kidney, liver, heart, pancreas, lung, skin graft and islets of langerhans, hepatocyte, stem cell precursor and differentiation.
3. the process of claim 1 wherein that the factor of described inhibition dendritic cell maturation is a kind of inhibitor of Nf κ B nuclear translocation.
4. the method for claim 3, the inhibitor of wherein said Nf κ B nuclear translocation is a kind of analog or the derivant of deoxyspergualin.
5. the process of claim 1 wherein that the factor of described inhibition dendritic cell maturation activates the Th2 cytokine that one or more plant dependence NF-AT.
6. the process of claim 1 wherein that the factor of described inhibition dendritic cell maturation suppresses the Th1 cytokine that one or more plant dependence Nf κ B.
7. the process of claim 1 wherein that the mortifier of described dendritic cell maturation is a kind of solubility IL-17 receptor Fc fusion rotein.
8. the process of claim 1 wherein that the mortifier of described dendritic cell maturation is a kind of glucocorticoid.
9. the process of claim 1 wherein that the mortifier of described dendritic cell maturation is the bonded a kind of blocker of tumor necrosis factor.
10. the process of claim 1 wherein that the mortifier of described dendritic cell maturation is the bonded a kind of blocker of granulocyte macrophage colony stimulating factor.
11. the process of claim 1 wherein that the mortifier of described dendritic cell maturation is the bonded a kind of blocker of IL-12p70.
12. the process of claim 1 wherein that the mortifier of described dendritic cell maturation is the bonded a kind of blocker of interleukin 1 β.
13. the process of claim 1 wherein that the mortifier of described dendritic cell maturation is anti-CD154 part.
14. the process of claim 1 wherein, give described receptor at least once with the factor of described inhibition dendritic cell maturation.
15. the process of claim 1 wherein, give described receptor in the preceding factor of transplanting with described inhibition dendritic cell maturation.
16. the process of claim 1 wherein that described immunotoxin is a kind of at the T cellular immunization toxin CD3 epi-position, anti-.
17. the method for claim 1, described method further are included in the preceding donor that a kind of factor that suppresses dendritic cell maturation is given graft of the described graft of gathering.
18. a kind of method that aspect inducing immune tolerance, plays the synergistic factor of screening with immunotoxin; Comprise:
(a) a kind of donor graft is transplanted in the receptor;
(b) give described receptor a kind of immunotoxin, reduce the T cell mass of described receptor thus;
(c) give described receptor the described factor to be screened;
(d) obtain a sample that comprises dendritic cell; And
(e) be determined in the described sample and express or can be by the percent of the dendritic cell of abduction delivering mature dendritic cell specific marker; Wherein low percent shows synergism.
19. method of screening the factor that suppresses dendritic cell maturation; Described method comprises:
(a) obtain an immaturity dendritic cell group by portion from a sample experimenter, that comprise dendritic cell;
(b) existing described waiting to screen under the situation of the factor, cultivate described cell mass; And
(c) mensuration is expressed or can be by the percent of the dendritic cell of abduction delivering mature dendritic cell specific marker; Wherein low percent shows the inhibition to dendritic cell maturation.
20. a compositions, described compositions comprise a kind of immunotoxin and a kind of factor that suppresses dendritic cell maturation.
21. the compositions of claim 18, wherein said immunotoxin are a kind of at the T cellular immunization toxin CD3 epi-position, anti-.
22. the compositions of claim 19, the factor of wherein said inhibition dendritic cell maturation are a kind of inhibitor of Nf κ B nuclear translocation.
23. the compositions of claim 19, the factor of wherein said inhibition dendritic cell maturation activate one or more and plant the Th2 cytokine that relies on NF-AT.
24. suppressing one or more, the compositions of claim 19, the factor of wherein said inhibition dendritic cell maturation plant the Th1 cytokine that relies on Nf κ B.
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CN105531289A (en) * 2013-02-01 2016-04-27 全氏生物有限公司 Anti-CD83 antibodies and use thereof
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