WO1996029082A1 - A process of prolonging organ allograft survival - Google Patents
A process of prolonging organ allograft survival Download PDFInfo
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- WO1996029082A1 WO1996029082A1 PCT/IB1996/000400 IB9600400W WO9629082A1 WO 1996029082 A1 WO1996029082 A1 WO 1996029082A1 IB 9600400 W IB9600400 W IB 9600400W WO 9629082 A1 WO9629082 A1 WO 9629082A1
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- A—HUMAN NECESSITIES
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Definitions
- Acute organ allograft rejection may result from responses associated with the pro-inflammatory cytokines IL-2, IFN-y, and TNF- , derived from Thl cells. Down-regulation of Thl activity, therefore, may be a useful immunomodulatory therapy. It is also well known that infection by certain parasitic organisms can modulate the balance between Thl and Th2 activity. By way of example, Sher and coworkers have demonstrated that a depression of Thl-type responses can be achieved by helminth infection (Sher el al, J. Immunol.. 147:2713, 1991). Helminth infection can also result in up-regulation or stimulation of Th activity. Nematode induced up- regulation can encompass stimulation of IgE (and IgGl in mice or IgG4 in humans), mast cell hyperplasia and eosinophilia in all species, including humans.
- the present invention provides a process of prolonging organ allograft survival in an organism comprising down- regulating Thl activity in the organism.
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Abstract
The present invention provides a process of prolonging organ allograft survival in an organism comprising down-regulating Th1 activity in the organism. The down-regulation of Th1 activity is accomplished either by infecting the organism with an effective Th2 up-regulating amount of a nematode or by administering to the organism an effective Th2 up-regulating amount of a soluble extract of a nematode. Exemplary and preferred nematodes for use in a process of the present invention are of the genus Nippostrongylus, Trichuris, Ascaris or Caenorhabditis. Most preferred is the nematode Nippostrongylus brasiliensis. A process of the present invention is particularly useful in prolonging kidney allograft survival.
Description
A PROCESS OF PROLONGING ORGAN ALLOGRAFT SURVIVAL
Description
Technical Field of the Invention The field of the present invention is organ allograft survival.
More specifically, the field of the present invention is prolongation of organ allograft survival. Organ allograft survival is prolonged by down-regulating Thl activity in an organism receiving an organ allograft.
Background of the Invention
The development of novel immunosuppressive drugs has caused a dramatic increase in the short term survival of organ transplants in recent years. The use of such drugs, however, is associated with side effects such as opportunistic infections, tumors and ultimately, chronic rejection.
The recent description of two subsets of T helper cells (Th), with different cytokine secretion profiles and activities, may provide a new paradigm for immυnoregulation of organ allograft rejection (Mosmann et al, Immunol. Today. 8:223, 1987). The two Th cell subsets, designated Thl and Th2, can be characterized on the basis of their respective cytokine production profiles. Thl cells produce and secrete interferon-gamma (IFN- γ), lymphotoxin (LT) and interleukin-2 (IL-2). On the other hand, Th2 cells produce and secrete interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-6 (IL-6) and interleukin-10 (IL-10).
Acute organ allograft rejection may result from responses associated with the pro-inflammatory cytokines IL-2, IFN-y, and TNF- , derived from Thl cells. Down-regulation of Thl activity, therefore, may be a useful immunomodulatory therapy. It is also well known that infection by
certain parasitic organisms can modulate the balance between Thl and Th2 activity. By way of example, Sher and coworkers have demonstrated that a depression of Thl-type responses can be achieved by helminth infection (Sher el al, J. Immunol.. 147:2713, 1991). Helminth infection can also result in up-regulation or stimulation of Th activity. Nematode induced up- regulation can encompass stimulation of IgE (and IgGl in mice or IgG4 in humans), mast cell hyperplasia and eosinophilia in all species, including humans.
It is well known that the immune modulation associated with helminth infection is unrelated to the worm antigens per se. For example, greater than 80 percent of the IgE generated during Nippostrongylus brasiliensis (N. brasiliensis) infection was found not to be directed to N. brasiliensis (Jarrett et al, Clin. Exp. Immunol.. 24:326, 1976).
Such induced up-regulation may be due to the cross-regulatory actions of the Thl/Th2 system. The Thl and Th2 subsets have been found to be cross-regulatory with respect to differentiation and activity. By way of example, cytokines produced "by Th2 cells (e.g., IL-4 and IL-10) inhibit Thl cell growth and cytokine production and ablate the effects of Thl cytokines
(e.g., IFN-y) on their targets, while IFN-y inhibits Th2 function (Powrie et al, Immunol. Today. 14:270, 1993).
The concept of resistance or susceptibility being related to Thl/Th2 balance has also been suggested in a variety of other models, including AIDS, and even successful pregnancy. The finding of pro- inflammatory cytokines IL-2, IFN-y, TNF-α and IL-6 in rejecting kidney allografts lends support to the hypothesis that Thl-type T cells orchestrate the immune response, which culminates in rejection. It likely that a
Thl Th2 balance is established within the graft which changes over time, differs among individuals, and is dependent on the treatment administered but that the cellular mechanisms behind graft rejection, such as infiltration by macrophages and CTL, are consistent with the activities of Thl cells.
Brief Summary of the Invention
In one aspect, the present invention provides a process of prolonging organ allograft survival in an organism comprising down- regulating Thl activity in the organism.
In a preferred embodiment, the down-regulation of Thl activity is accomplished by infecting the organism with an effective Th2 up- regulating amount of a nematode.
In another preferred embodiment, the down-regulation of Thl activity is accomplished by administering to the organism an effective Th2 up-regulating amount of a soluble extract of a nematode.
Exemplary and preferred nematodes for use in a process of the present invention are of the genus Nippostrongylus, Trichuris, Ascaris or
Caenorhabditis. More preferred are Nippostrongylus brasiliensis, Trichuris muris, Trichuris suis, Ascaris lumbricoides, Ascaris suum or Caenorhabditis elegans. Most preferred is Nippostrongylus brasiliensis (N. brasiliensis). A process of the present invention is particularly useful in prolonging kidney allograft survival.
Brief Description of the Drawings
In the drawing, which forms a portion of the specification:
FIG. 1 shows IgGl levels following N. brasiliensis infection or treatment with N. brasiliensis extract
Detailed Description of the Invention I. The Invention
Infection with parasites such as nematodes induces strong IgE responses not restricted to parasite antigens. In addition, certain helminths have profound immunomodulatoiy effects on infected animals, inducing strong Th2 responses while diminishing Thl activity. The present invention provides that infection of organisms with nematodes or the administration of soluble nematode extracts to organisms significantly prolonged organ allograft survival in those organisms.
II. Process of Prolonging Allograft Survival In one aspect, the present invention provides a process of prolonging organ allograft survival in an organism comprising down- regulating Thl activity in the organism.
As used herein, the phrase "organ allograft" means a body organ graft from a donor organism of the same species but a different genotype than the recipient organism. As used herein, the term "organ" means a vascularized internal organ such as heart, liver and kidney. An exemplary and preferred organ allograft is a kidney allograft. As used herein, an organ does not include skin. Skin differs from vascularized organs contemplated by the present invention because a substantial component of the graft vascular supply is derived from the donor rather than the recipient. Thus, skin allografts are much less susceptible to certain immune-mediated injuries (Bradley et al, Immunol. Today. 13:434, 1992).
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As used herein, the terms "up-regulation" and "down- regulation" and their grammatical equivalents mean, respectively, stimulation and inhibition. Thus, down-regulation of Thl activity means a depression or inhibition of the cascade of physiological responses that accompany a Thl cytokine production profile and up-regulation of Th2 activity means a stimulation or enhancement of the cascade of physiological responses that accompany a Th2 cytokine production profile.
In a preferred embodiment, the down-regulation of Thl activity is accomplished by infecting the organism with an effective Th2 up- regulating amount of a nematode. An effective amount is that amount necessary to bring about the desired effect (e.g., down-regulation of Thl activity). Means for determining an effective amount are well known in the art. By way of example, an organism is infected with various amounts of a particular nematode and the level of Thl activity monitored. An effective amount will depend inter alia, as is well known in the art, on the nature of the organism being injected and the nature of the particular nematode used. Exemplary effective amounts using rodents and the nematode N. brasiliensis are set forth hereinafter in the Examples.
In another preferred embodiment, the down-regulation of Thl activity is accomplished by administering to the organism an effective Th2 up-regulating amount of a soluble extract of a nematode. As set forth above, means for determining an effective amount of a soluble extract are well known and readily ascertainable by a skilled artisan. Means for making a soluble extract are also well known in the art (See, e.g.. Lee et al, Immunology. 55:721, 1985). By way of example, nematodes are homogenized in an aqueous medium such as saline (0.9% NaCl). The medium can further comprise buffers such as phosphate. Homogenization
can be accomplished by mechanical means or other disruptive means such as sonication. The homogenate is typically cleared of particυlate matter using ultracentrifugation. The nematode is then filter sterilized to remove bacteria.
A soluble nematode extract can be administered to the organism by parenteral routes of administration as is well k own in the art. The extract can be dispersed or suspended in a physiologically acceptable diluent prior to administration. A preferred route of administration is subcutaneous. An extract can be administered prior to, simultaneously with or after organ transplantation. In a preferred embodiment, an extract is administered prior to, simultaneously with and after transplantation. One of ordinary skill in the art can readily determine the optimum administration schedule for a given transplant and treatment regimen.
Any nematode that down -regulates Thl activity can be used in a process of the present invention. Exemplai and preferred nematodes for use in a process of the present invention are of the genus Nippostrongylus, Trichuris, Ascaris or Caenorhabditis. More preferred are Nippostrongylus brasiliensis, Trichuris muris, Trichuris suis, Ascaris lumbricoides, Ascaris siium or Caenorhabditis elegans. Most preferred is Nippostrongylus brasiliensis (N. brasiliensis).
A process of the present invention prolongs allograft survival when compared to allograft survival performed in the absence of nematode treatment. In other words, a process of the present invention improves or increases survival time of the allograft.
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A detailed description of the use of a process of the present invention to prolong kidney allograft survival is set forth hereinafter in the Examples. Briefly, rats were infected with N. brasiliensis (Nb) or treated with a soluble extract of N. brasiliensis (Nb extract) and received a kidney allograft. The survival time of the kidney allograft was increased from 9.7 ±
1.2 days (no treatment) to 32.0 ± 10.0 days (Nb infection) and 21.5 ± 4.6 days (Nb extract treatment). By day 5 post transplant, untreated allografts contained a substantial mononuclear cell infiltrate and kidney destruction was advanced. In contrast, kidneys transplanted into Nb treated animals had only a mild cellular infiltrate and retained normal architecture. FACS analysis revealed a significant decrease in the number of CD8+ cells infiltrating Nb treated grafts. Preliminary RT-PCR analysis of mRNA expression by graft-infiltrating cells indicated that the production of IL-4 was up-regulated in Nb-treated kidneys as opposed to untreated allografts.
In additional studies, Nb treatment was associated with substantial and significant increases in IgGl levels (See Example 2).
The following Examples illustrate preferred embodiments of the present invention and are not limiting of the claims or specification in any way.
EXAMPLE 1: Kidney Allograft Survival
Lewis (LEW.RT11) and Brown Norway (BN, RT1") rats were chosen as recipients and donors, respectively. Male rats were purchased from Harlan Sprague Dawley (Indianapolis, IN) and provided with water and rat chow ad libitum. Animals receiving a N. brasiliensis infection were injected with 3500 third stage infective larvae subcutaneously four days prior to transplantation. Animals receiving the nematode products were injected
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subcutaneously, at day -4, 0 and +4 (with day 0 being the day of transplant) with 200 worm equivalents of adult worm homogenate. All procedures were performed under sodium pentobarbital anaesthesia (65 mg/kg).
The left kidney of the donor (BN) rat was perfused in situ with cold (4°C) saline, mobilized, and removed. It remained in cold saline during the preparation of the recipient. Following left nephrectomy of the Lewis recipient, the BN kidney was transplanted in a heterotopic position. Ureteric reconstruction in these experiments was achieved by end-to-end anastomosis. Four days after the transplants, the recipients were re- anaesthetized and a right native nephrectomy was performed. Animals were sacrificed when they showed signs of morbidity due to failure of the transplanted kidney.
Graft survival data are shown below in Table 1.
TABLE 1 Kidney Allograft Survival Following Nematode Infection
Treatment Survival (days) Mean ± SD
No treatment 10, 8, 11, 11 9, 8, 11, 9, 10 9.7 ± 1.2
Nb infection 34, 27, 34, 23 25, 34, 25, 54 32.0 ± 10.0
Nb extract 30, 21, 22, 20 16, 20 21.5 ± 4.6
These results clearly show a significant prolongation of kidney allograft survival in animals given either a N. brasiliensis infection or soluble
woπn extract. In untreated animals kidneys survived a mean of only 9.7 ± 1.2 (mean ± SD, n=9) days, whereas kidneys in nematode infected rats retained functional capacity much longer, resulting in a mean survival time of 32.0 ± 10.0 (mean ± DS, n-8) days, with one animal retaining grafted kidney function up to 54 days post transplant. In animals treated with the worm extract the survival was also significantly longer (mean 21.5 ± 4.6).
In addition to graft survival the histological appearance of the transplanted kidneys was assessed in the control versus N. brasiliensis treated recipients 5 days after transplant. Transplanted kidneys were flushed with cold saline and cut into 2-3 mm thick slices before fixation in formalin. Sections were taken and stained with hematoxylin and eosin using standard protocols.
The results demonstrate clear differences between the kidneys taken from the N. brasiliensis infected and the control groups. The intensity of the infiltration was, in a blinded evaluation, found to be much more extensive in the control group when compared to the N. brasiliensis infected group. In the control group. there was extensive infiltration of the interstitia by mononuclear cells and evidence of damage to the tubular endothelium in some tubules. In the kidneys isolated from N. brasiliensis infected recipients, in contrast, there was only a small amount of mononuclear infiltrate around major vessels and almost no interstitia] infiltrate. Kidney architecture in the N. brasiliensis infected recipients was virtually normal.
These data show that infection of rats by the nematode N brasiliensis or treatment with N. brasiliensis extracts significantly prolonged kidney allograft survival across a known strong histocompatibility barrier.
This prolongation likely results from the ability of N. brasiliensis to strongly activate Th2 responses with a resultant inhibition of Thl activity.
EXAMPLE 2: Regulation Of IgGl Response Bv Nematodes Increases in the serum levels of total (non-specific) IgE and
IgGl or IgG4 are associated with nematode infections in mice and humans respectively. There are several points where this response can be regulated. One of such, is during the process of Immunoglobulin class switch.
A group of five BALB/c mice was infected with 500 infective larvae of the nematode Nippostrongylus brasiliensis and a second group of five BALB/c mice (age matched) was injected subcutaneously with an extract from N. brasiliensis (Adult Worm Homogenate, AWH) at a concentration of 200 worm equivalent emulsified in Freund's Incomplete Adjuvant. The levels of total IgGl in the serum obtained from the blood taken from these mice, were measured weekly for ten weeks, by IgGl capture ELISA.
The data showed clearly that, the nematode extract, AWH induces significant increases fn the production of total serum IgGl. The result agrees with the massive increase in total IgE and IgGl levels associated with infection with the larvae. As shown in FIG. 1, a ten fold increase in the IgGl levels was observed. Prior to the injection of AWH, the total serum IgGl level in the mice was 0.25mg/ml. This level increased continuously from week 1 (0.30mg/ml) through week 4 (1.15 mg/ml). Further increases in the serum IgGl level upon re-injection with the nematode extract at week 4, were also observed. It reached its maximum (2.15 g/ml) at week 7, before it started to decline. N. brasiliensis extract AWH, also induced significant increase in total IgGl levels in vivo.
Claims
1. A process of prolonging organ allograft survival in an organism comprising down-regulating Thl activity in the organism.
2. The process of claim 1 wherein down-regulating Thl activity is accomplished by infecting the organism with an effective Th2 up- regulating amount of a nematode.
3. The process of claim 1 wherein down-regulating Thl activity is accomplished by administering to the organism an effective Th2 up-regulating amount of a soluble extract of a nematode.
4. The process of claim 2 wherein the nematode is of the genus Nippostrongylus, Trichuris, Ascaris or Caenorhabditis.
5. The process of claim 3 wherein the nematode is of the genus Nippostrongylus, Trichuris, Ascaris or Caenorhabditis.
6. The process of claim 4 wherein the nematode is of the genus Nippostrongylus.
1. The process of claim 5 wherein the nematode is of the genus Nippostrongylus.
8. The process of claim 6 wherein the nematode is Nippostrongylus brasiliensis.
9. The process of claim 7 wherein the nematode is Nippostrongylus brasiliensis.
10. The process of claim 1 wherein the organ is kidney.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/913,622 US6090413A (en) | 1996-03-25 | 1995-03-23 | Process of prolonging organ allograft survival |
| AU53449/96A AU5344996A (en) | 1995-03-23 | 1996-03-25 | A process of prolonging organ allograft survival |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US40921195A | 1995-03-23 | 1995-03-23 | |
| US08/409,211 | 1995-03-23 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1996029082A1 true WO1996029082A1 (en) | 1996-09-26 |
Family
ID=23619511
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IB1996/000400 WO1996029082A1 (en) | 1995-03-23 | 1996-03-25 | A process of prolonging organ allograft survival |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU5344996A (en) |
| CA (1) | CA2216090A1 (en) |
| WO (1) | WO1996029082A1 (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000025810A2 (en) * | 1998-11-03 | 2000-05-11 | University Of Nottingham | Immunomodulatory factors for immunosuppressant and antiallergic treatment |
| EP1041994A1 (en) * | 1997-12-31 | 2000-10-11 | University of Iowa Research Foundation | Use of parasitic biological agents for prevention and control of autoimmune diseases |
| EP1069135A1 (en) * | 1998-03-31 | 2001-01-17 | Nisshin Flour Milling Co., Ltd. | Proteins having immunomodulatory activity and remedies for immunological diseases |
| JP2012092045A (en) * | 2010-10-27 | 2012-05-17 | Yamaguchi Univ | Immunopotentiator derived from helminth parasite |
| EP3107558B1 (en) * | 2014-02-19 | 2020-04-01 | University of Southampton | Treating infection |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0045237A1 (en) * | 1980-07-28 | 1982-02-03 | BERRI BALZAC Société dite: | Immunosuppressive compound, process for isolating it and its therapeutical use |
| WO1993017698A1 (en) * | 1992-03-04 | 1993-09-16 | Schering Corporation | Use of interleukin-10 to suppress graft-vs.-host disease |
| WO1995024425A1 (en) * | 1994-03-11 | 1995-09-14 | Board Of Regents, The University Of Texas System | Immunomodulatory trichinella substances |
-
1996
- 1996-03-25 AU AU53449/96A patent/AU5344996A/en not_active Abandoned
- 1996-03-25 WO PCT/IB1996/000400 patent/WO1996029082A1/en active Application Filing
- 1996-03-25 CA CA002216090A patent/CA2216090A1/en not_active Abandoned
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0045237A1 (en) * | 1980-07-28 | 1982-02-03 | BERRI BALZAC Société dite: | Immunosuppressive compound, process for isolating it and its therapeutical use |
| WO1993017698A1 (en) * | 1992-03-04 | 1993-09-16 | Schering Corporation | Use of interleukin-10 to suppress graft-vs.-host disease |
| WO1995024425A1 (en) * | 1994-03-11 | 1995-09-14 | Board Of Regents, The University Of Texas System | Immunomodulatory trichinella substances |
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| A. SHER ET AL.: "PRODUCTION OF IL-10 BY CD4+ LYMPHOCYTES CORRELATES WITH DOWN-REGULATION OF Th1 CYTOKINE SYNTHESIS IN HELMINTH INFECTION.", JOURNAL OF IMMUNOLOGY, vol. 147, no. 8, 15 October 1991 (1991-10-15), BALTIMORE US, pages 2713 - 2716, XP002009494 * |
| D.L. LEDINGHAM ET AL.: "PROLONGATION OF RAT KIDNEY ALLOGRAFT SURVIVAL BY NEMATODES.", TRANSPLANTATION, vol. 61, no. 2, 27 January 1996 (1996-01-27), BALTIMORE, US, pages 184 - 188, XP000577116 * |
| N.E. STREET ET AL.: "FUNCTIONAL DIVERSITY OF T LYMPHOCYTES DUE TO SECRETION OF DIFFERENT CYTOKINE PATTERNS.", FASEB JOURNAL FOR EXPERIMENTAL BIOLOGY, vol. 5, no. 2, February 1991 (1991-02-01), BETHESDA, MD US, pages 171 - 177, XP002009493 * |
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| JP2011016840A (en) * | 1997-12-31 | 2011-01-27 | Univ Of Iowa Research Foundation | Use of parasitic biological agent for prevention and control of autoimmune disease |
| JP4733830B2 (en) * | 1997-12-31 | 2011-07-27 | ユニヴァーシティー オブ アイオワ リサーチ ファンデーション | Use of parasitic agents for the prevention and control of autoimmune diseases |
| JP2014129390A (en) * | 1997-12-31 | 2014-07-10 | Univ Of Iowa Research Foundation | Use of parasitic biological agents for prevention and control of autoimmune diseases |
| EP2255820A1 (en) * | 1997-12-31 | 2010-12-01 | University Of Iowa Research Foundation | Use of parasitic biological agents for prevention and control of autoimmune diseases |
| EP1749534A3 (en) * | 1997-12-31 | 2007-02-21 | University Of Iowa Research Foundation | Use of parasitic biological agents for prevention and control of autoimmune diseases |
| US6764838B2 (en) | 1997-12-31 | 2004-07-20 | University Of Iowa Research Foundation | Use of parasitic biological agents for prevention and control of autoimmune diseases |
| EP1041994A4 (en) * | 1997-12-31 | 2003-02-19 | Univ Iowa Res Found | Use of parasitic biological agents for prevention and control of autoimmune diseases |
| US7250173B2 (en) | 1997-12-31 | 2007-07-31 | University Of Iowa Research Foundation | Use of parasitic biological agents for prevention and control of autoimmune diseases |
| EP1041994A1 (en) * | 1997-12-31 | 2000-10-11 | University of Iowa Research Foundation | Use of parasitic biological agents for prevention and control of autoimmune diseases |
| JP2001527048A (en) * | 1997-12-31 | 2001-12-25 | ユニヴァーシティー オブ アイオワ リサーチ ファンデーション | Use of parasitic agents for prevention and control of autoimmune diseases |
| EP1069135A1 (en) * | 1998-03-31 | 2001-01-17 | Nisshin Flour Milling Co., Ltd. | Proteins having immunomodulatory activity and remedies for immunological diseases |
| EP1069135A4 (en) * | 1998-03-31 | 2004-10-20 | Nisshin Seifun Group Inc | Proteins having immunomodulatory activity and remedies for immunological diseases |
| US6521263B1 (en) | 1998-11-03 | 2003-02-18 | University Of Nottingham | Immunomodulatory factors for immunosuppresant and antiallergic treatment |
| WO2000025810A2 (en) * | 1998-11-03 | 2000-05-11 | University Of Nottingham | Immunomodulatory factors for immunosuppressant and antiallergic treatment |
| WO2000025810A3 (en) * | 1998-11-03 | 2000-08-10 | Univ Nottingham | Immunomodulatory factors for immunosuppressant and antiallergic treatment |
| JP2012092045A (en) * | 2010-10-27 | 2012-05-17 | Yamaguchi Univ | Immunopotentiator derived from helminth parasite |
| EP3107558B1 (en) * | 2014-02-19 | 2020-04-01 | University of Southampton | Treating infection |
Also Published As
| Publication number | Publication date |
|---|---|
| CA2216090A1 (en) | 1996-09-26 |
| AU5344996A (en) | 1996-10-08 |
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