Prolonged allograft survival by the inhibition of costimulatory CD2 signals but not by modulation of CD48 (CD2 ligand) in the rat.
The CD2 receptor is an important costimulatory molecule in T cell activation. Its ligand CD48 in rodents is supposed to be a homologue of human CD58, because of its similarities in structure and distribution. We evaluated the immunosuppressive activity of CD2/CD48-directed therapy in vitro and in vivo for the efficacy in prolonging rat heart allograft survival in a high responder transplant model. CD2-directed monoclonal antibody (mAb) therapy significantly prolonged median survival time to 45 days (P < 0.001). Suppression was mediated by down-modulation of CD2 below 20% on lymph node cells without considerable cell depletion. In contrast, CD48 mAb could not prolong graft survival. Rejection occurred in the presence of complete CD48 modulation and, therefore, despite disruption of the CD2-CD48 interaction. CD48 mAb failed to inhibit lymphocyte activation via a mitogenic pair of CD2 mAbs and inhibited mixed lymphocyte reaction (MLR) only by an unspecific mechanism. In conclusion, our results suggest a negative regulatory signal transduction by inhibitory CD2 mAbs and argue against a pivotal role of mere disruption of the CD2-CD48 interaction in CD2-mediated immunosuppression.
Sido
B
B
Department of Surgery, University of Heidelberg, Germany.
Otto
G
G
Zimmermann
R
R
Müller
P
P
Meuer
S
S
Dengler
T J
TJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D015703:Antigens, CD / Q000502:physiology*; D018801:CD2 Antigens / Q000502:physiology*; D000071178:CD48 Antigen; D006085:Graft Survival; D016027:Heart Transplantation; D016130:Immunophenotyping; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018801:CD2 Antigens; D000071178:CD48 Antigen; C000604065:CD48 protein, human; C000604067:Cd48 protein, rat