Anti-CD2 and anti-CD3 monoclonal antibodies synergize to prolong allograft survival with decreased side effects.
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)
Chavin
K D
KD
Department of Surgery, Medical University of South Carolina, Charleston.
Qin
L
L
Lin
J
J
Kaplan
A J
AJ
Bromberg
J S
JS
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology*; D018801:CD2 Antigens; D017252:CD3 Complex / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D004357:Drug Synergism; D005260:Female; D005434:Flow Cytometry; D006085:Graft Survival / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D011247:Pregnancy; D011971:Receptors, Immunologic / Q000276:immunology*; D013577:Syndrome; D014184:Transplantation, Homologous / Q000009:adverse effects / Q000276:immunology*
D000911:Antibodies, Monoclonal; D000945:Antigens, Differentiation, T-Lymphocyte; D018801:CD2 Antigens; D017252:CD3 Complex; D016207:Cytokines; D011971:Receptors, Immunologic