WO1981000813A1 - Activites de suppression et d'augmentation de production d'anti-corps ige - Google Patents

Activites de suppression et d'augmentation de production d'anti-corps ige Download PDF

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WO1981000813A1
WO1981000813A1 PCT/US1980/001231 US8001231W WO8100813A1 WO 1981000813 A1 WO1981000813 A1 WO 1981000813A1 US 8001231 W US8001231 W US 8001231W WO 8100813 A1 WO8100813 A1 WO 8100813A1
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mice
ige
responses
serum
sfa
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D Katz
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Scripps Clinic Res
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14—Blood; Artificial blood
    • A61K35/16—Blood plasma; Blood serum

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  • IgE-mediated allergic diseases constitute a major health problem with consequences that not only affect the physical well-being of affected individuals but also impose a substantial economic impact on both individual and society alike. While significant advances in the pharmacologic approach to the therapy of such disorders have been made in the past, the bulk of such approaches are aimed at the effector phase of the allergic reaction and, hence, are largely transient in the symptomatic relief afforded by such therapy. Immunologic or "immunotherapeutic" approaches have been attempted for many years but have not resulted in any universally effective solutions to this problem.
  • Successful immunotherapy constitutes therapy that is aimed at, and effective in, the induction phase of the allergic response, namely that which tackles the problem by sufficiently diminishing or abolishing IgE synthesis.
  • the classical "hyposensitization" approach has been only variably successful, although some instances of dramatic success have been observed, for reasons that are not totally clear although, no doubt, the quality of allergenic extracts employed most likely plays an important determining role, among other things. This somewhat unfortunate state of affairs may very likely be soon coming to an end.
  • the IgE antibody system plays an important defense role against certain offending exogenous antigens, particularly those which gain access through mucoepithelial and epithelial linings such as the respiratory and gastrointestinal tract and skin.
  • What is particularly unique about the IgE system is the inherent amplification of its physiological capacity.
  • IgE molecules become specifically and avidly bound to receptors displayed on the surface membranes of tissue-fixed mast cells and circulating basophils, and since such cells are actually minute factories of potent pharmacological mediators, it is possible for small numbers of IgE molecules to go a long way in exerting the desired biological effect.
  • IgE antibody responses could be sufficient to provide protection to the individual without resulting in undesirable and/or deleterious reactions. Indeed, as will become clear in the following specification, it appears that this is precisely how the system is designed to operate under normal circumstances. However, it will also be clear that the balance of control of IgE synthesis is so delicate that it becomes susceptible to certain perturbations that can upset the balance and thereby result in production of higher than necessary quantities of IgE which, in turn, can be translated into symptomatic manifestations. Summary
  • Figure 1 is a graph depicting the selective suppression of irradiation-enhanced primary IgE antibody responses of low responder SJL mice by passive administration of CFA-induced suppressive factor of allergy (SFA).
  • mice were either not irradiated (group I) or irradiated with 250 rads (groups IV) shortly prior to carrier preimmunization with 2 ⁇ g of KLH in alum on day -8.
  • groups III and IV were injected with serum from normal SJL mice or from CFA-immune SJL donors, respectively; such injections consisted of 0.1 ml of the respective sera per injection given 4 times spaced at 12-hour intervals over a 48-hour period.
  • all mice were primarily immunized with 2 ⁇ g of DNP-KLH in alum.
  • the IgE and IgG anti-DNP antibody responses on day 10 after primary sensitization are presented as % of the respective untreated control responses (group I) with the actual titers listed beside the control bars.
  • Figure 2 is a graph depicting the separation of suppressive and enhancing activities for IgE antibody responses of low responder SJL mice by affinity chromatography on Con A-Sepharose.
  • mice Groups of SJL mice were employed in the protocol summarized on the left side of this figure.
  • the injection schedules of the various serum or ascitic fluid samples indicated were identical to those described in Figure 1.
  • the IgE anti-DNP antibody responses on day 14 after primary immunization with 10 ⁇ g of DNP-ASC in alum are illustrated as % of the control response with the group I control value listed beside the corresponding bar.
  • Figure 3 is a graph depicting the discovery that Con A-Sepharose-fractionated SFA from C57BL/5 donors, unlike unfractionated B6 ascitic fluid, displays unrestricted capacity to suppress irradiation-enhanced IgE responses of SJL mice.
  • FIG. 1 is a graph depicting the suppression of irradiation-enhanced IgE responses of high responder CAF 1 mice with Con A-Sepharose-fractionated SFA from CAF 1 ascites fluid.
  • mice were employed in the protocol summarized on the left side of this figure.
  • the injection schedules of the various serum or ascitic fluid samples indicated were identical to those described in Figure 1.
  • the IgE anti-DNP antibody responses on day 10 after primary immunization with 2 ⁇ g of DNP-KLH in alum are illustrated as % of the control response with the group I control value listed beside the corresponding bar.
  • Figure 5 is a graph depicting the demonstration of SFA activity in Con A-Sepharose-fractionated high responder A/J ascites effective in suppressing irradiation-enhanced responses of low responder SJL mice.
  • mice were either not pretreated (open circles) or pretreated with 250 rads irradiation shortly before preimmunization with 2 ⁇ g of KLH in alum on day -7.
  • days -1 and 0 three groups of mice were injected with either unfractionated or Con A-Sepharose-fractionated ascites fluid from high responder A/J mice, using a similar injection schedule as that described in Figure 1.
  • all mice were primarily immunized with 2 ⁇ g of DNP-KLH in alum, and a secondary challenge with the same antigen and dose was administered on day 48.
  • the IgE anti-DNP antibody responses are illustrated as PCA titers.
  • Figure 6 is a graph depicting the discovery that SFA activity in unfractionated and Con A-Sepharose- fractionated high responder A/J ascites suppresses irradiation-enhanced IgE responses of A/J mice but the damping effect does not persist.
  • High responder A/J mice were employed in a protocol identical to that described in Figure 5.
  • Preparations of unfractionated and Con A-Sepharose-fractionated A/J ascites fluid were identical to those used in the experiment presented in Figure 5.
  • the IgE anti-DNP antibody responses are illustrated as PCA titers.
  • Figure 7 is a graph depicting the possible pathogenesis of "allergic breakthrough".
  • Figure 8 is a graph depicting the discovery that the height of IgE antibody production persists at elevated levels for long periods of time following irradiation-induced allergic breakthrough in SJL mice.
  • mice were either not pretreated (open circles) shortly before preimmunization with 2 ⁇ g of KLH in alum on day -7. All mice were primarily immunized on day 0 with 2 ⁇ g of DNP-KLH in alum and given a secondary challenge with the same antigen and dose on day 60.
  • the IgE anti-DNP antibody responses are illustrated as PCA titers at the indicated intervals over a 7-month period.
  • Figure 9 is a graph depicting the persistence of both "allergic breakthrough" due to EFA and/or X-irradiation and suppressive effects of SFA in low responder C57BL/6 mice.
  • SJL mice were employed in a protocol identical to that described in Figure 5 with the exception that the dose of irradiation employed was 350 R and the SFA-enriched and EFA-enriched Con A-Sepharose-fractionated ascites fluids were obtained from syngeneic SJL donor mice.
  • Figure 10 is a graph depicting the specificity of "allergic breakthrough" resulting from low dose irradiation and concomitant sensitization of low responder SJL mice.
  • mice were either not pretreated (open symbols) or pretreated with 350 R irradiation (closed symbols) shortly before preimmunization with 2 ⁇ g of KLH in alum on day -7.
  • all four groups of mice were primarily immunized with 2 ⁇ g of DNP-KLH in alum.
  • one group each of u ⁇ irradiated and irradiated mice were secondarily challenged with 2 ⁇ g of DNP-KLH in alum, while a second unirradiated and irradiated group were primarily immunized at that time with 10 ⁇ g of OVA in alum.
  • the IgE anti-DNP antibody responses through both primary and secondary responses and the primary anti-OVA IgE responses on days 28 and 35 are illustrated as PCA titers.
  • Figure 11 is a graph depicting the discovery that human peripheral blood lymphocytes produce an SFA-like activity in certain 2-way mixed lymphocyte cultures which can suppress irradiation-enhanced IgE responses of low responder SJL mice.
  • mice were employed in a protocol identical to that described in Figure 1 with the exception of the type of materials injected to test for suppressive activity on IgE antibody production.
  • One group (group III) was treated with Con A-fractionated SFA from SJL donors while four groups (group IV-VII) were treated with four different preparations of supernatant fluids from human two-way MLC reactions.
  • the IgE anti-DNP antibody responses on day 10 after primary immunization with 2 ⁇ g of DNP-KLH in alum are presented as % of the control response with the group I control value listed beside the corresponding bar.
  • Figure 12 is a graph depicting the discovery that sub-optimal low dose X-irradiation facilitates expression of enhancing effects of passive serum on IgE antibody responses of high responder (SJL x BALB/c)F- 1 mice.
  • mice (SJL x BALB/c)F 1 mice were used in the type of protocol summarized on the left of this figure.
  • the IgE anti-DNP antibody responses of groups of 4 mice each on day 15 after immunization with 10 ⁇ g of DNP-ASC in alum are illustrated as % of control with the group I control value listed beside the corresponding bar. Although not shown, there were no significant differences in IgG anti-DNP antibody responses among the various groups.
  • Figure 13 is a graph depicting the discovery that sub-optimal low dose X-irradiation facilitates expression of enhancing effects of passive serum on IgE antibody responses of low responder SJL mice.
  • mice Groups of SJL mice were used in a protocol similar to that summarized on the left side of this figure.
  • the IgE anti-DNP antibody responses on day 10 after primary immunization are shown in the top panel and are presented as actual PCA titers of each respective group.
  • the boxed-in area in the top panel illustrates results obtained in a separate experiment, also performed in SJL mice, in which the optimal (350 R) dose of X-irradiation was used for elicitation of enhanced primary IgE responses.
  • the values given are the responses obtained in groups of SJL mice either not treated or treated with the same serum or ascites preparations used in the present experiment.
  • mice On day 18, all mice were boosted with 10 ⁇ g of DNP-ASC in alum; no additional X-irradiation or passive serum transfusion was administered at that time.
  • the IgE antibody responses 10 days after secondary challenge (day 28) are illustrated in the bottom panel.
  • Figure 14 is a graph depicting the discovery that IgE antibody responses of low responder SJL mice can be either enhanced or suppressed by the CFA depending on when it is administered relative to sensitization.
  • mice were either not irradiated (upper panel) or exposed to 350 R (lower panel) on day -7 shortly prior to carrier preimmunization with 2 ⁇ g of KLH in alum.
  • One group of each type i.e. unirradiated and irradiated
  • all mice were primarily immunized with 2 ⁇ g of DNP-KLH in alum.
  • Figure 15 is a graph depicting the persistence of suppression of IgE antibody production in SJL mice following secondary sensitization administered three weeks after a single treatment with suppressive factor of allergy (S.F.A. ).
  • S.F.A. suppressive factor of allergy
  • Groups of SJL mice were employed in the protocol summarized on the left side of this figure.
  • Carrier preimmunization consisted of 10 ⁇ g of ASC in alum.
  • the IgE anti-DNP antibody responses on day 14 after primary immunization are illustrated in the top panel as % of control response, with the group I control value listed beside the corresponding bar.
  • the IgE anti-DNPantibody responses 7 days after secondary challenge (day 32) are illustrated in the bottom panel, again as % of control response.
  • Figure 16 is a graph depicting the persistence of the "allergic" and “non-allergic" phenotypes induced by various means in low responder SJL mice.
  • mice were either not irradiated (open symbols) or exposed to 350 R (closed symbols) on day -7, shortly before carrier preimmunization with 2 ⁇ g of KLH in alum. Also on day -7, two groups of mice (open and closed triangles) were inoculated with 0.25 ml of a 4:1 CFA:saline emulsion i.p. On day 0, an additional two groups of mice (open and closed squares) were inoculated with a similar preparation of CFA i.p. All mice were primarily immunized with 2 ⁇ g of DNP-KLH on day 0 and subsequently sensitized in the same manner for secondary challenge on day 78. The IgE anti-DNP antibody responses on days 7, 11 and 17 and again on days 78 and 88 are illustrated as PCA titers.
  • Figure 17 is a graph depicting the discovery that administration of CFA concomitant with primary sensitization reverses suppression of irradiation-enhanced IgE responses by allogeneic cell transfusions to low responder SJL mice.
  • mice were irradiated with 350 R on day -7 shortly prior to carrier preimmunization with 2 ⁇ g of KLH in alum.
  • two groups of mice were inoculated with a 4:1 CFA:saline emulsion i.p. (open and closed squares).
  • One of these groups (closed squares) and another group (closed circles) were also inoculated i.v. with 30 x 10 6 allogeneic C57BL/6 spleen cells.
  • a control group (open circles) received neither CFA nor allogeneic cells.
  • All groups of mice were primarily immunized with 2 ⁇ g of DNP-KLH on day 0 and subsequently secondarily challenged in the same manner on day 78.
  • the IgE anti-DNP antibody responses on days 7, 11 and 17 and again on days 78 and 88 are illustrated as PCA titers.
  • Figure 18 is a graph depicting the specificity of "allergic breakthrough" resulting from low dose X-irradiation and concomitant sensitization of low responder SJL mice.
  • mice were either not irradiated (open symbols) or irradiated with 350 R (closed symbols) on day -7. Certain of these groups were also preimmunized with 2 ⁇ g of KLH at this time, while others were not as indicated in the individual panels. On day 0, mice in the upper five panels were primarily immunized with 2 ⁇ g of DNP-KLH in alum; those in the bottom panel were immunized with 10 ⁇ g of OVA in alum.
  • mice were secondarily immunized with either 2 ⁇ g of DNP-KLH, 2 ⁇ g of KLH, 10 ⁇ g of DNP-OVA or 10 ⁇ g of OVA, all administered in alum i.p. as indicated in the individual panels.
  • the IgE antibody responses specific for either DNP, KLH or OVA are illustrated as PCA titers.
  • Figure 19 is a graph depicting the analysis of lipoprotein fractions of CFA-immune serum in suppression of irradiation-enhanced primar nd of CFA-induced ascitic fluid in suppression o adoptive secondar IgE antibody responses in SJL mice.
  • Figure 20 is a graph depicting the discovery that suppressive material in SJL ascitic fluid is heat stable and precipitable by ammonium sulfate.
  • Figure 21 is a graph depicting the chromatographic fractionation of suppressive material in SJL ascitic fluid on Bio-Gel A1.5M.
  • Figure 22 is a graph depicting the failure to absorb active molecule (s) in CFA-immune C57BL/6 mice with specific anti-H-2 b alloantiserum immunoadsorbents.
  • Figure 23 is a graph depicting the discovery that molecules in SJL ascitic fluid which suppress adoptive secondary IgE responses in SJL mice can be absorbed with anti- ⁇ 2 m and anti-whole serum antibodies, but not by ant ⁇ -H-2 s alloantibodies or antimouse Ig antibodies.
  • Inbred mice provide a good experimental system for analysis in studies on regulation of IgE antibody production.
  • inbred mice can be divided into categories of low and high IgE responder phenotypes.
  • Levine and Vaz (6) made the important observation that different inbred strains of mice display easily distinguishable IgE response patterns following antigen sensitization in that certain strains of mice respond with production of relatively high quantities of specific IgE antibodies, whereas other strains produce considerably lower, or undetectable, antibody responses in this clkss following comparable modes of immunization.
  • these low responses are restricted to the IgE class, since these latter strains of mice produce normal quantities of antibodies to the same antigens in other Ig classes.
  • the experiment illustrated in Figure 1 demonstrates the type of observation which represented a significant first step in the ultimate evolution of conceptual perspectives concerning both the regulation of IgE antibody production and how at least certain of the manifestations of the individual displaying the allergic phenotype may come about.
  • the basic experimental design is summarized on the left side of Figure 1 and for the most part reflects the type of experimental protocol employed for most of the studies presented hereafter. In brief, groups of mice are either not exposed or exposed to 250 rads of whole body irradiation on day -8 (or day -7 in other instances).
  • mice are preimmunized with unconjugated carrier protein, either keyhole limpet hemocyanin (KLH) , as in Figure 1, or in other cases the extract of As oaris s uum (ASC) each of which are administered in aluminum hydroxide gel (alum).
  • KLH keyhole limpet hemocyanin
  • ASC As oaris s uum
  • CFA mycobacterial-containing complete Freund's adjuvant
  • the injections are given at 9-12 hour intervals by alternating intravenous and intraperitoneal routes until a total of 4 doses (usually 0.1 ml per injection) have been given.
  • primary hapten-carrier immunization is given intraperitoneally with 2 ,4-dinitrophenyl (DNP) conjugated to the same carrier (i.e., KLH or ASC) as that used for carrier preimmunization.
  • DNP 2 ,4-dinitrophenyl
  • Mice are then bled at varying intervals thereafter and their serum analyzed for levels of circulating IgE and IgG anti-DNP antibodies.
  • the experiment in Figure 1 was conducted in low responder SJL mice.
  • mice As illustrated by group I, these mice, unless otherwise manipulated, develop very low primary IgE anti-DNP antibody responses, while responses in the IgG class are essentially normal in magnitude.
  • responses in the IgG class are essentially normal in magnitude.
  • the consequence is a rather dramatic alteration in their normal IgE response pattern to one that is at least as high, and sometimes higher, than the type of response typically made by mice of the high responder phenotype
  • variable quantities of SFA can be found in the serum of normal donor mice, particularly those of the low IgE responder phenotype; the effects of CFA, or certain other manipulations as described hereinafter, are related to the abilities of such materials to stimulate production of exaggerated quantities of SFA in such donor mice.
  • the biological effect of SFA is completely nonspecific in the sense that IgE responses elicited by any number of antigens can be effectively suppressed by appropriate doses of SFA.
  • SFA displays very high activity even when administered in minute quantities.
  • SFA is produced by living animals and is biologically active when passively transferred to living recipients, thereby underscoring the physiological relevance of this potent factor. Table 1 summarizes the properties of SFA as known at the present time (14-17).
  • mice exposed to low level irradiation displayed an "allergic breakthrough" pattern of primary IgE antibody production (closed circles) which was not appreciably affected by the administration of either unfractionated A/J ascites fluid (closed circles) which was not appreciably affected by the administration of either unfractionated A/J ascites fluid (closed squares) or the fraction of this A/J ascites preparation which adsorbed to Con A-Sepharose and was then eluted from the column with ⁇ -methyl-D-glucopyranoside (open triangles).
  • IgE antibody production should remain elevated in the allergic zone even though the damping mechanism has returned to its normal threshold level.
  • the graph has been divided into non-allergic (lower) and allergic (upper) zones at a cutoff point of a PCA titer of 80 (in evaluating data obtained from many hundreds of low responder mice in terms of IgE antibody production, this was the highest titer even attained by low responder mice which had not been otherwise manipulated to convert their response pattern to the high responder phenotype).
  • SJL mice which are converted to high responder status by whole body irradiation show clear breakthrough patterns of primary IgE antibody production. The height of IgE production tends to remain at elevated levels in such mice and, of course, following secondary stimulation on day 60, such mice manifest a clear secondary elevation of IgE production.
  • mice have been divided, for convenience, into the upper, or allergic, zone and the lower, or non-allergic, zone in parallel with the allergic breakthrough model presented in Figure 7. It is clear from these responses that two groups of mice manifested allergic breakthrough, namely those mice exposed to irradiation and not treated otherwise, and those mice both exposed to irradiation and also transfused with EFA. Conversely, two other groups displayed IgE response patterns which were of the nonallergic phenotype. These groups were, respectively, the unirradiated controls and the groups of irradiated mice transfused with SFA. The important point to note in these response patterns is that they are retained throughout the course of observation, even as long as three months later following secondary sensitization with the same antigen.
  • mice were either not irradiated, as indicated by the open symbols , or irradiated on day -7 , as indicated by the closed symbols .
  • Carrier preimmunization was carried out at that time with KLH fo llowed by primary immuni zation with DNP-KLH on day 0 .
  • mice were either secondarily challenged with DNP-KLH or given a primary immunization with ovalbumin ( OVA) , as indicated.
  • OVA ovalbumin
  • mice show very nice break thro ugh -type anti-DNP antibody responses (the same is also true for anti-KLH responses , but the data is not included in this figure) .
  • unirradiated mice likewise failed to display appreciable primary IgE anti-OVA antibody responses when initial sensitization to this antigen was administered on day 18.
  • IgE antibody synthesis Experimental evidence has been obtained in the laboratory of Ishizaka (2 ) that one approach along these lines might involve the induction of antigen-specific suppressor T cells .
  • Ishizaka and colleagues have demons trated that adminis tration of certain chemically-denatured antigens tends to preferentially induce specific suppressor T cells which , in turn, can effectively diminish IgE antibody responses specific for the antigen employed.
  • the practical drawbacks to this approach relate to the necessity for 1) having accurately defined the specific allergen concerned with any individual's allergic disorder, and 2) tailoring such therapy on a more-or-less individual basis from one patient to the next.
  • this approach might have considerable limitations in those individuals manifesting multiple systemic allergies or in those individuals for which the specific offending allergen cannot be accurately defined.
  • mice used in all experiments the rats employed for measurement of IgE antibody responses by passive cutaneous anaphylaxis (PCA) , immunizations , methods for administering whole body ionizing X-irradiation, procedures for treatment of mice with CFA and preparation of CFA- induced ascites , the regimen for administration of serum or ascites to test mice , and the methods for measuring serum IgE and IgG DNP-specific antibodies were identical to those described in the preceding studies on this system (14 , 15 , 16) .
  • PCA passive cutaneous anaphylaxis
  • Anti-H-2 alloantisera Anti-H-2 antisera were prepared by hyperimmunization of recipient mice with donor spleen and lymph node cells inoculated at weekly intervals ip with 25 x 10 cells per mouse per injection . The resulting antisera were analyzed for specific alloantibody activity using a microcytotoxicity assay and distinguishing dead from live cells by trypan blue exclusion. The following antisera were prepared : BlO .BR anti-BlO . D2 (anti- H-2 d ) , BlO . D2 anti-BlO (anti-H-2 b ) and (C57BL/6 x A) F 1 anti-SJL ( anti-H-2 S ) . The samples of these anti-sera used for ii ⁇ munoadsorbents in the present studies were cytotoxic for >90% of specific target lymphocytes at dilutions of 1:16 or 1:32.
  • Rabbit antimouse immunoglobulins antiserum Rabbit antimouse Ig was prepared by hyperimmunizing
  • New Zealand red rabbits (Triple R Rabbitry, Manasquan, N.J.) with 2-5 mg of a gamma globulin-rich fraction of mouse sera initially in CFA (DIFCO Laboratories, Detroit, Mich.) and subsequently in IFA every 2-3 weeks for 3 months or more.
  • CFA DIFCO Laboratories, Detroit, Mich.
  • IFA IFA every 2-3 weeks for 3 months or more.
  • Rabbit antirat ⁇ 2 m Rabbit antirat ⁇ 2 m. Purified rat 3 2 m was a generous gift from Dr. M. D. Poulik, William Beaumont Hospital, Royal Oak, Michigan. New Zealand red rabbits were immunized with 100 ⁇ g of rat 3 2 m in CFA intradermally and subcutaneously and boosted 3 months later with 50 ⁇ g of ⁇ 2 m, again in CFA, followed 2 months thereafter by 25 ⁇ g of ⁇ 2 m' precipitated with alum and administered ip. The resulting sera precipitated purified rat ⁇ 2 m and reacted weakly, prior to absorption, with normal rat serum proteins.
  • the anti- ⁇ 2 m antisera Prior to use, the anti- ⁇ 2 m antisera were absorbed with an excess of glutaraldehyde crosslinked normal rat serum as described below. The absorbed anti- ⁇ 2 m gave only one line of precipitation with purified rat ⁇ 2 m and failed to precipitate unrelated rat serum proteins upon analysis by immunoelectrophoresis. Previous studies have documented that antirat ⁇ 2 m cross-reacts completely with mouse ⁇ 2 m (31). Rabbit anti-whole mouse serum. New Zealand red rabbits were immunized with CFA-immune serum from BALB/c mice inoculated with 0.2 ml of CFA ip 6 days prior to bleeding.
  • Each rabbit received an initial immunization of 0.5 ml of CFA-immune BALB/c serum emulisified in CFA and administered intradermally.
  • a second immunization consisting of 0.5 ml of CFA-immune BALB/c serum, was administered in IFA 17 days after the first.
  • the rabbits were bled 2 weeks later and the serum stored frozen until used.
  • the antiserum displayed strong precipitation reactions against mouse serum.
  • the serum was centrifuged at 47,000 rpm for 20-22 hr using a Spinco SW 50.1 rotor. The top one-third of the tube was collected as the lipoproteinrich fraction and the bottom two-thirds was recovered as the lopoprotein-free fraction; both fractions were dialyzed for 4 days against lipoprotein buffer consisting of 0.15 M NaCl, 0.05 mM EDTA, and 0.005% ⁇ -tocopherol, pH 7.4 (32), and then injected immediately into mice. The SJL ascitic fluid was fractionated into LDL
  • Ammonium sulfate precipitation of ascitic fluid was added to ascitic fluid to final concentrations of 33%, 45%, or 50%. The mixtures were stirred at 4°C for 1 hr after which the precipitate was collepted by centrifugation, redissolved in PBS (pH 7.2) to the original starting volume and then dialyzed extensively against PBS in the cold. The resulting fractions were stored frozen until used. Chromatographic fraction of ascitic fluid.
  • a fraction of ascitic fluid precipitated with ammonium sulfate at 45% saturation was dialyzed against 0.01 M borate-buf fered saline (pH 8.01 and then applied to a column of Bio-Gel A1.5M (Bio-Rad Laboratories, Richmond, Calif.) equilibrated in borate-buf fered saline. The column was run at a flow rate of 12.5 ml/hr and fractions of approximately 3 ml each collected. Optical density at 280 ⁇ g of each fraction was monitored by an LKB Uvicord absorptiometer (LKB Instruments, Rockville, Md.).
  • the polymerized sera were homogenized in a tissue grinder, v/ashed extensively with PBS, and then stored in PBS containing 0.02% sodium azide at 4°C until use. Unfractionated SJL ascitic fluid was absorbed directly with excess immunoadsorbents in a batch-wise procedure similar to that described previously (35) . Each immunoadsorbent, prepared from 4.0 ml of antiserum, was used to absorb 1.3 ml of ascitic fluid. Results In early 1978, a shift was experienced in the optimal X-irradiation dose for enhancing IgE antibody responses in low responder mice.
  • the optimum dose was 150 R when a tube-type X-ray unit was used or 250 R with a cesium irradiator. Recently the optimal dose for converting low responders to high IgE responder status shifted to the somewhat higher dose of 350 R (using the same cesium irradiator).
  • Sub-Optimal Low Dose X-Irradiation Facilitates Expression of Enhancing Effects of Passive Serum on IgE Antibody Responses.
  • mice exposed to the (now) suboptimal dose of irradiation i.e. 250 R
  • mice exposed to the (now) suboptimal dose of irradiation provided an excellent vehicle for observing substantial enhancing activity of serum molecules on IgE antibody production. Details of representative experiments are presented below. a) Enhancing Effects of Serum on Responses of High Responder Mice. In the experiment presented in Figure 12, (SJL x )
  • mice (groups II-VI) inadvertently received a suboptimal dose (250 R) of X-irradiation, there was no enhancement in IgE antibody synthesis in group II irradiated animals as compared to the group I unirradiated controls.
  • donor serum significantly enhanced the primary IgE antibody responses of these high responder mice. This was true irrespective of whether donor serum came from normal (groups III and V) or CFA-primed (groups IV and VI) mice of either parental or F 1 hybrid type. Note the striking 16-fold enhancement manifested by recipients of normal F 1 serum (group V) and the almost comparable 8-fold enhancement in recipients of CFA-primed F 1 serum (group VI). No significant differences in the IgG anti-DNP antibody responses were observed among the different groups. b) Enhancing Effects of Serum on Responses of Low Responder Mice.
  • mice in group V, treated with another batch of CFA-primed SJL serum and those in group VI which were treated with a preparation of SJL ascitic fluid (the fraction precipitated with 50% ammonium sulfate) developed clearly detectable levels of IgE anti-DNP antibodies.
  • the active fraction of SFA activity is precipitable by ammonium sulfate.
  • CFA serum #1 did not significantly affect the irradiation-enhanced responses elicited with this optimal dose of irradiation.
  • CFA serum #2 and, in particular, the sample of ascitic fluid were capable of exerting significant suppressive effects on the irradiation-enhanced responses elicited in this subsequent experiment; the importance of these differences in activity will be discussed below.
  • mice in groups I-VI that developed following exposure to a secondary challenge with DNP-ASC on day 18. It. is to be emphasized that no other manipulation was performed with these mice since their initial treatment at the outset of the experiment other than the administration of the secondary dose of DNP-ASC. When these mice were bled 10 days later (day 28), the biological influence of their previous passive serum treatment could then be even more fully appreciated. Thus, neither mice in groups I or II, not previously given passive serum or ascites, displayed an ability to produce other than very meager IgE responses following secondary challenge with secondary IgE responses; indeed, the magnitudes of responses in groups V and VI are in every way comparable to the types of secondary responses we typically observe in high IgE responder mice.
  • IgG anti-DNP antibody responses were not significantly different among these various groups of mice.
  • IgE Antibody Responses of Low Responder Mice Can be Either Enhanced or Suppressed by CFA Depending on When it is Administered Relative to Sensitization.
  • mice Low responder SJL mice were either not irradiated (top panel) or exposed to 350 R X-irradiation (bottom panel) on day -7 shortly prior to preimmunization with 2 ⁇ g of KLH in alum. Also at this time one group each of unirradiated and X-irradiated mice were inoculated with 0.25 ml of CFA i.p. On day 0 all mice were primarily immunized with 2 ⁇ g of DNP-KLH in alum; on the same day a second group each of unirradiated and X-irradiated mice were inoculated with 0.25 ml of CFA i.p. All mice were then bled on days 7, 11 and 17 after primary immunization and their serum IgE anti-DNP antibody levels determined.
  • mice exposed to 350 R but not inoculated with CFA displayed typical enhanced IgE response patterns (open circles).
  • similarly irradiated mice which were inoculated with CFA on the same day as X-irradiation displayed blunted IgE responses, particularly early after sensitization, with some evidence of very slight recovery on day 17 (closed triangles); note that the peak response developed by such mice was 16-fold lower than the peak response developed by the X-irradiated mice not treated with CFA.
  • mice which were given CFA on the same day as primary sensitization with DNP-KLH (closed squares) displayed significantly enhanced IgE responses at the earliest day of bleeding (4-fold higher than their corresponding X-irradiated controls not given CFA) and this response pattern continued to rise throughout the course of the response.
  • Persistence of the Re-Established Damping Mechanism Four groups of SJL mice were incorporated in the standard protocol for eliciting X-irradiation-enhanced IgE antibody production and reversal of such enhanced responses by passive serum transfusion (1,2) as summarized on the left side of Figure 15. It should be noted that in this experiment the dose of
  • X-irradiation employed was 250 R, since this experiment was carried out prior to the shift in optimal X-irradiation dose described in the preceding study.
  • low responder SJL mice developed enhanced primary IgE anti-DNP antibody responses following exposure to this dose of X-irradiation (c.f. group II versus group I); these enhanced responses, although not. diminished by normal serum (group III) were almost totally suppressed by passive transfusion of serum from CFA-primed SJL donor mice (group IV).
  • mice All four groups of mice were rested until day 25 at which time a secondary challenge with DNP-ASC was administered; no additional serum treatment was given at that time.
  • the IgE antibody responses of these mice 7 days after secondary challenge (day 32) are shown in the lower panel. Two points are evident from the day 32 data; first, the magnitude of IgE antibody synthesis in mice exposed 40 days earlier (day -8) to low dose X-irradiation was still 16-fold higher (groups II and
  • mice in group IV to develop secondary IgE anti-DNP antibody responses following challenge on day 25 is particularly noteworthy since these mice were given only one course of SFA containing serum on days -1 and 0.
  • mice Four groups of low IgE responder C57BL/6 mice were placed in the standard protocol; in this and all subsequen experiments, the low dose of X-irradiation employed for eliciting enhanced IgE production was 350 R. Three of the four groups were exposed to 350 R just prior to carrier preimmunization with KLH on day -8, and two of these groups were given passive transfusions of ascites fluid known to be enriched in either SFA or EFA activity. All mice were primarily immunized with DNP-KLH on day 0. As shown in Figure 9, referred to above, exposure to this dose of X-irradiation resulted in the usual enhanced response (closed circles) as contrasted to the unirradiated controls (open circles).
  • mice given ascites fluid enriched in EFA followed primary response patterns similar to those of the irradiated, but untreated, group.
  • Pertinent to this study are the results obtained when these four groups of mice were first bled and then given secondary challenge with DNP-KLH on day 90.
  • all mice had persistent levels of detectable IgE anti-DNP antibodies prior to secondary challenge; three of these, groups, including the irradiated, but untreated, group displayed levels that were in the non-allergic zone.
  • the fourth group, treated with EFA on days -1 and 0, maintained a rather high titer clearly still in the allergic zone.
  • mice Following secondary challenge, only two groups displayed titers that fell into the allergic zone, namely the irradiated, but untreated, animals and those which were treated with EFA.
  • the unirradiated, untreated control mice although displaying a slight rise in titer following secondary challenge still remained in the non-allergic zone in terms of level of response.
  • those mice treated with SFA not only remained in the non-allergic zone but actually showed a decline in IgE anti-DNP antibody level following secondary challenge.
  • mice Six groups of low responder SJL mice were used in the experiment summarized in Figure 16. Three groups were not exposed to low dose X-irradiation (350 R, open symbols), whereas the remaining three groups were exposed to 350 R on day -7 (closed symbols) shortly prior to carrier pre-immunization with KLH. One group of each type (i.e. unirradiated versus irradiated) were either not given CFA (open and closed circles), given CFA on day -7 (open and closed triangles) or on day 0 (open and closed squares). All mice were primarily immunized with DNP-KLH on day 0 and given a secondary challenge on day 78 with the same antigen. The data presented in Figure 16 illustrate several important points.
  • mice failed to display any evidence of secondary response, as was true of their irradiated counterparts (closed triangles) in contrast to the moderate secondary response (although still in the non-allergic zone) manifested by the unirradiated, untreated controls.
  • mice Two groups (closed symbols) were injected with 30 x 10 6 allogeneic C57BL/6 spleen cells intravenously (also on day 0) while two groups (open symbols) received no allogeneic cells.
  • One group each of mice which did not receive (open squares) and those which did receive (closed squares) allogeneic spleen cells were also inoculated with CFA on day 0. All four groups of mice were later secondarily challenged with DNP-KLH on day 79.
  • mice exposed to low dose X-irradiation at the time of carrier pre-immunization displayed breakthrough IgE anti-DNP antibody responses during the primary course as contrasted with their unirradiated counterparts. Following secondary challenge on day 18, these mice maintain high IgE responses both to DNP and to KLH; the unirradiated mice continued to produce only modest levels of antibodies of both specificities.
  • secondary challenge with unconjugated KLH similarly elicited breakthrough patterns of IgE production to this antigen in mice exposed to low dose X-irradiation, but not in their unirradiated counterparts.
  • mice In the third panel from the top, are the results obtained in mice either not exposed or exposed to X-irradiation on day -7, but not pre-immunized with unconjugated KLH at that time. It is clear that neither group of mice developed IgE responses either to DNP in the primary or to either DNP or KLH in the secondary that displayed a breakthrough pattern. This indicates that the timing of sensitization relative to exposure to low dose X-irradiation is quite critical for the phenotypic expression of the breakthrough response pattern; a delay of as little as one week between X-irradiation and sensitization has the result of leaving such mice in the non-allergic zone in terms of their IgE antibody responses.
  • mice in neither the irradiated or unirradiated groups responded to such secondary challenge with development of anti-OVA antibody levels rising into the allergic zone.
  • Irradiated mice in both instances maintained levels of anti-DNP IgE antibody in the allergic zone, but this was true irrespective of whether secondary challenge was conducted with DNP-OVA or OVA alone.
  • the lower-most panel merely illustrates the capacity td elicit irradiationenhanced anti-OVA IgE responses in mice subjected to 350 R shortly prior to primary immunization with OVA, as contrasted to their unirradiated control counterparts.
  • Human peripheral blood lymphocytes were obtained from normal donors and isolated by sedimentation velocity on Ficoll-Hypaque. Lymphocytes obtained from multiple donors in this fashion were then cultured in 2-way MLC reactions at a density of 1.5 x 10 6 cells of each donor type per ml in volumes totaling 14 ml per culture for a period of 3-4 days. The culture supernatants were harvested after this period of time by centrifugation and the culture supernatants so obtained were concentrated 3-fold by ultrafiltration on Amicon PM-10 ultrafiltration membranes. Such concentrated culture supernatants were administered to mice in the same doses as those described previously for the administration of serum or ascites fluid preparations. Studies with Concanavalin A-Sepharose-Fractionated Ascites from Low and High IgE Responder Mice. a) The damping activity of low responder SFA is not strain-specific.
  • Figure 4 also referred to earlier, demonstrates that, once fractionated on Con A-Sepharose, the existence of SFA activity in such high responder mice can be readily demonstrated.
  • the experiment summarized in Figure 4 was conducted in high responder CAF, mice. Being high responders, these mice developed considerably higher primary IgE responses under ordinary circumstances (group I). Nevertheless, exposure to low dose whole body irradiation results in significant enhancement of such responses (group II).
  • mice exposed to low level irradiation displayed an "allergic breakthrough" (5,11,12) pattern of primary IgE antibody production (closed circles) which was not appreciably affected by the administration of either unfractionated HA ascites fluid (closed squares) or the fraction of this A/J ascites preparation which adsorbed to Con A-Sepharose and was then eluted from the column with ⁇ -methyl-D-glucopyranoside (open triangles).
  • the latter result is precisely what one would expect since, as shown previously (4), the fraction eluted from Con A-Sepharose in this manner is the one that is enriched for EFA activity.
  • mice that were treated with the Con A-Sepharose effluent, i.e., that fraction enriched for SFA activity, displayed totally depressed IgE responses (closed triangles).
  • IgE responses displayed totally depressed IgE responses (closed triangles).
  • Serum molecules suppressing IgE responses are nondialyzable.
  • mice were either not exposed or exposed to 250 R X-irradiation shortly before preimmunization with 10 ⁇ g of ASC in alum on day -8.
  • mice in groups III-VII received 4 injections of the indicated serum samples (0.1 ml of serum diluted to 0.5 ml with sterile saline per injection) spaced at 12-hour intervals using alternating iv and ip routes of administration.
  • mice Shortly after the 3rd injection all mice (including groups I and II) were primarily immunized with 10 ⁇ g of DNP-ASC in alum (day 0).
  • the IgE and anti-DNP responses on day 10 are shown. No significant differences in IgG responses were observed among the various groups.
  • mice were primarily immunized with 10 ⁇ g of DNP-ASC in alum.
  • IgE anti-DNP antibody responses of groups of four mice each on day 10 after primary immunization are illustrated in the top right panel as percent of the control response with the actual control value listed beside the corresponding bar (group I). Although not illustrated, there were no significant differences in the IgG anti-DNP antibody responses among the various groups.
  • recipient SJL mice were irradiated with 675 R and then injected with 25 x 10 6 spleen cells obtained from DNP-ASC-primed SJL donor mice.
  • mice in groups II-V were given the materials indicated, again in 4 divided doses at 12-hour intervals over a 48-hour period.
  • the IgE anti-DNP antibody responses in groups of 4 mice each on day 7 after secondary challenge are illustrated as percent of the control response in group I, with the actual group I values listed beside the corresponding bar. Again, no significant differences in IgG antibody responses were observed among the various groups.
  • the SJL ascitic fluid was exposed to 56°C for 30 minutes or precipitated with ammonium sulfate at final concentrations of 33% and 50%, and the resulting materials tested for suppressive activity on adoptive secondary IgE responses of SJL mice.
  • Recipient SJL mice were irradiated with 675 R and then injected intravenously with 25 x 10 6 DNP-ASC-primed SJL spleen cells.
  • Secondary challenge consisting of 10 ⁇ g of DNP-ASC in alum, was given shortly after cell transfer on day 0.
  • mice in groups II-VI were injected with the materials indicated according to the schedule described for lipoprotein analysis. IgE and IgG anti-DNP antibody responses on day 7 after secondary challenge are presented as percent of control responses in group I recipient mice with the actual
  • the adoptive secondary response was completely suppressed by administration of untreated ascitic fluid as well as ascitic fluid that had been subjected to heat inactivation.
  • the fractions of ascitic fluid precipitated by, respectively, 33% and 50% (NH 4 ) 2 S0 4 retained all of the suppressive activity manifested by unfractionated ascitic fluid (groups IV and V) .
  • the supernatant of ascitic fluid not precipitated with 50% (NH 4 ) 2 S0 4 failed to exert any suppressive activity on adoptive secondary IgE responses (group VT).
  • Bio-Gel A1.5M Five fractions (A-E) were obtained from the eluate and analyzed for suppressive activity in the adoptive secondary system ( Figure 21). SJL recipientg mice were irradiated with 675 R and injected with 25 x 10 6
  • mice were either not treated or treated with either unfractionated (group II), 45% ammonium sulfateprecipitated (group III) ascites fluid or the indicated fractions recovered from a Bio-Gel A1.5M column according to the schedule described for lipoprotein analysis.
  • IgE and IgG anti-DNP antibody responses on day 7 following transfer and secondary challenge are illustrated as percent of the control responses; the control IgE response (group I) is indicated beside the corresponding bar.
  • the control IgG response (not illustrated) was 449 ⁇ g/ml.
  • SJL ascitic fluid and its 45% (NH 4 ) 2 S0 4 -precipitated fraction were quite effective in suppressing the secondary IgE response in SJL mice (groups II and III).
  • Immunological Characterization of the Active Suppressive Molecules The control IgG response (not illustrated) was 449 ⁇ g/ml.
  • SJL ascitic fluid and its 45% (NH 4 ) 2 S0 4 -precipitated fraction were quite effective in suppressing the secondary IgE response in SJL mice (groups II and III).
  • Experiment II were irradiated with 675 R and then injected intravenously with 25 x 10 DNP-ASC-primed SJL spleen cells. Secondary challenge, consisting of 10 ⁇ g of DNP-ASC in alum, was given shortly after cell transfer on day 0. On days 1 and 2, mice in Groups II-VII (Exp. I) and II-VI (Exp. II) were injected with the materials indicated according to the schedule described for lipoprotein analysis. IgE anti-DNP antibody responses on day 7 after secondary challenge are presented as percentage of control responses in the corresponding Group I recipient mice with the actual IgE values listed beside the corresponding bars of these control groups. There were no significant differences in IgG anti-DNP antibody responses among the various groups in either experiment.
  • the suppressive factors of allergy, or SFA surely must be physiologically important because (1) their presence and quantity seems to parallel the magnitude of IgE antibody synthesis permissible in a given mouse; (2) passive administration of serum rich in SFA can effectively ablate IgE antibody responses that have been heightened by various manipulations; and (3) the activity of SFA is strain-specific suggesting that it adheres to precise control mechanisms involving "self-specificity" that now appears to be a characteristic feature of many cell-cell interactions in the immune system.
  • SJL ascites fluid was precipitated with 50% saturated ammonium sulfate, reconstituted to original volume and dialyzed extensively against phosphate-buffered saline (PBS). 3 ml of this material was applied to a 1.5 x 15 cm Concanavalin A-Sepharose (Pharmacia Fine Chemicals, Piscataway, N.J.) column equilibrated with PBS and eluted at a flow rate of 1.5 ml/min. The unbound fraction (effluent) was collected and the gel bed washed thoroughly with PBS. The material bound to the column was eluted with ⁇ -methyl-D-glucopyranoside (50 mg/ml).
  • PBS phosphate-buffered saline
  • Tada T Regulation of reaginic antibody formation is animals. Prog Allergy 19:122-170, 1975
  • Levine BB, Vaz NM Effect of combinations of inbred strain antigen, and antigen dose on immune responsiven and reagin production in the mouse. Int Arch Allergy Appl Immunol 30:156-163, 1970
  • Curtiss LK Edgington TS (1978) Identification of a lymphocyte surface receptor for low density liproprotein inhibitor, and immunoregulatory species of normal human serum low density liproprotein. J Clin Invest 61:1298.

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Identification, caracterisation et separation de facteurs de suppression d'allergie (SFA) et de facteurs d'augmentation d'allergie (ESA) et application des SFA et ESA aux diagnostics et a la therapie.
PCT/US1980/001231 1979-09-24 1980-09-23 Activites de suppression et d'augmentation de production d'anti-corps ige WO1981000813A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2588476A1 (fr) * 1985-10-11 1987-04-17 Pasteur Institut Facteur inhibant la fixation des ige sur les mastocytes, procede d'obtention et applications
US5272255A (en) * 1985-01-26 1993-12-21 Ciba-Geigy Corporation Polypeptide factors from colostrum
US5843676A (en) * 1985-06-11 1998-12-01 Ciba-Geigy Corporation Purified immunoglobulin-related factor, novel monoclonal antibodies, hybridoma cell lines, processes and applications

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
Immunological Reviews, Volume 41, issued 1978, Copenhagen, Denmark, D.H. KATZ, the Allergic Phenotype: Manifestation of 'Allergic Breakthrough' and Imbalance in Normal 'Damping' of IgE antibody Production, pages 77-108. *
Journal of Allergy and Clinical Immunology, Volume 62 issued July 1978, St. Louise, Missouri, D.H. KATZ, Control of IgE antibody production by suppressor substances, pages 44-55. *
Journal of Experimental Medicine, Volume 140, issued 1974, New York, N.Y., D. ARMERDING, Activtion of T and B lymphocytes in Vitro, II. Bioloical and Biochemical Properties of an Allogenic Effect Factor (AEF) Active in Triggering specific B Lymphocytes, pages 19-37. *
Journal of Experimental Medicine, Volume 145, issued 1977, New York, NY. N. WATANABE, Suppression of IgE Antibody Production in SJL Mice, III Charaterization of a Supprecessor substance Extracted from Normal SJL Spleen Cells, pages 1501-1510. *
Journal of Immunology, Volume 117, issued November, 1976, Baltimore, Maryland, N. CHIORAZZI, Hapten-Specific IgE Antibody Responses in Mice, VI. Selective Enhancement of IgE Antibody Production by Low Doses of X-Irradiation and by Cyclophosphamide, pages 1629-1637. *
Journal of Immunology, Volume 118, issued February, 1977, Baltimore, Maryland, N. WATANABE, Suppression of IgE Antibody Production in SJL Mice, II. Expression of Ly-1 Antigen on Helper and Nonspecific Suppressor T Cells, pages 485-487. *
Journal of Immunology, Volume 120, issued June, 1978 Baltimore, Maryland, A.S. TUNG, Regulation of IgE Antibody Production by Serum Molecules, I. Serum from Complete Freund's Adjuvant-Immune Donors Suppreses Irradiation -Enhanced IgE Production in Low Responder Mouse Strains, pages 2050-2059. *
Journal of Immunology, Volume 120, issued June, 1978, Baltimore, Maryland, D.H. KATZ, Regulation of IgE Antibody Production by Serum Molecules, II. Strain-Specificity of the suppressive Activity of Serum from Complete Freund's Adjuvant-Immune Low Responder Mouse Donors, pages 2060-2067. *
Journal of Immunology, Volume 121, issued November 1978, Baltimore Maryland, T. KISHIMOTO, Regulation of Antibody Response in Different Immunoglobulin classes, IV. Properties and Functions of "IgE Class-Specific" Suppressor Factor(s) Released from DNP-Mycobacterum-Primed T Cells, pages 2106-2112. *
Nature, Volume 253 issued January 3, 1975, London, M. ZEMBALA, In vitro absorption and molecular weight of specific T-cell suppressor factor, pages 72-74. *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5272255A (en) * 1985-01-26 1993-12-21 Ciba-Geigy Corporation Polypeptide factors from colostrum
US5843676A (en) * 1985-06-11 1998-12-01 Ciba-Geigy Corporation Purified immunoglobulin-related factor, novel monoclonal antibodies, hybridoma cell lines, processes and applications
US5874228A (en) * 1985-06-11 1999-02-23 Novartis Ag Methods and kits for determining the levels of IGE-BF
FR2588476A1 (fr) * 1985-10-11 1987-04-17 Pasteur Institut Facteur inhibant la fixation des ige sur les mastocytes, procede d'obtention et applications

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