Anti-CD2 and anti-CD3 monoclonal antibodies synergize to prolong allograft survival with decreased side effects.

TitleAnti-CD2 and anti-CD3 monoclonal antibodies synergize to prolong allograft survival with decreased side effects.
Publication TypeJournal Article
Year of Publication1993
AuthorsChavin KD, Qin L, Lin J, Kaplan AJ, Bromberg JS
Date Published1993 Apr
KeywordsAnimals, Antibodies, Monoclonal, Antigens, Differentiation, T-Lymphocyte, CD2 Antigens, CD3 Complex, Cytokines, Drug Synergism, Female, Flow Cytometry, Graft Survival, Heart Transplantation, Lymphocyte Activation, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Inbred CBA, Pregnancy, Receptors, Immunologic, Syndrome, Transplantation, Homologous

Anti-CD3 monoclonal antibody suppresses immunity and prolongs allograft survival; however, it induces T cell activation and overproduction of soluble factors that result in a deleterious cytokine syndrome. Anti-CD2 mAb also prolongs allograft survival, by suppression of mature and precursor CD4 and CD8 T cells and NK cells, without an associated cytokine release. Because of the close physical and functional association of CD2 and CD3 on the T cell surface, we tested whether alpha CD2 mAb in combination with alpha CD3 mAb could act synergistically to prolong allograft survival, and whether the combination would affect the alpha CD3-associated cytokine syndrome. C57BL/6 (H-2b) hearts were transplanted to CBA (H-2k) recipients in a heterotopic nonvascularized model. Recipients received alpha CD2 (12-15) or alpha CD3 (145-2C11) mAb i.v. alone or in combination. Lymphocytes from treated animals were also analyzed by fluorescent flow cytometry and stimulated in vitro and assessed for proliferation and lymphokine production. Anti-CD2 and alpha CD3 each prolong allograft survival (mean survival time 22.4 +/- 1.0 and 27.4 +/- 3.3 days, respectively vs. 14.0 +/- 0.6 for control mAb, P < 0.001 for both vs. control). Combinations of mAbs show a more complicated interaction. Very low doses (1 microgram) of alpha CD2 and alpha CD3, which have no effect when given alone, are synergistic (16.5 +/- 1.3 days, P < 0.02). A high dose of alpha CD2 (100 micrograms), which is immunosuppressive, is additive with a moderate dose of alpha CD3 (10 micrograms), which is immunostimulatory. The two mAbs are again synergistic when a high dose of alpha CD2 (100 micrograms) is combined with a high dose of alpha CD3 (1 mg) (> 51.5 +/- 23.0 days, P < 0.001). Furthermore, high-dose alpha CD2 administered 48 h prior to high-dose alpha CD3 was a more effective combination for prolonging allograft survival than both antibodies administered simultaneously (67.1 +/- 10 vs. 35.8 +/- 0.7 days, P < 0.05). Anti-CD2 also diminishes the alpha CD3-associated cytokine syndrome, and prior in vivo treatment with alpha CD2 decreases the subsequent in vitro proliferative response to alpha CD3 and the alpha CD3-stimulated production of IL-2 and IL-4. Flow cytometry demonstrates that in general these mAbs do not deplete but leave T cell populations intact with altered receptor expression. These results show that the combination of alpha CD2 and alpha CD3 mAbs prolongs cardiac allograft survival in a synergistic fashion while decreasing the side effects of alpha CD3 mAb alone.(ABSTRACT TRUNCATED AT 400 WORDS)

Alternate JournalTransplantation
PubMed ID8097344
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