Long-term survival of hamster islet xenografts in mice under short-course treatment with nondepleting versus depleting anti-CD4 monoclonal antibodies.
Xenogeneic grafts provide a potential alternative to the current shortage of human organs for transplantation. However, the prevention of rejection and tolerance induction of xenografts still remain to be further explored. Islet xenografts appear more promising than vascularized whole organ xenografts and additionally also more resistant to the recurrence of autoimmune disease than allografts. Recently, the nondepleting monoclonal antibody (mAb), which blocks the CD4 molecule on lymphocytes, was reported to be able to induce tolerance in allotransplantation and CD4 positive cells were further confirmed to be a major factor responsible for cellular xenograft rejection. Therefore, we hypothesize that anti-CD4 nondepleting mAb could also be effective in protecting cellular xenografts and inducing unresponsiveness of recipients. We studied the effect of the nondepleting anti-CD4 mAb YTS177.9 on islet xenograft survival by using the hamster-to-mouse islet transplantation model. Results were compared with that of the depleting anti-CD4 mAb GK1.5 that was shown to have similar binding sites on the CD4 molecule to mAb YTS177.9. Our data show that mAb YTS177.9 did effectively prolong the survival of islet xenografts and, in addition, also successfully did induce long-term acceptance of 40% grafts after only three perioperative injections of 0.5 mg mAb per mouse. The average survival of the graft was markedly prolonged to >66.8+/-37.1 days compared with controls (8.3+/-1.4 days) or with the depleting anti-CD4 mAb GK1.5 (25.7+/-5.5 days). However, the latter displayed a more profound inhibition in in vitro and ex vivo mixed lymphocyte xenoreaction than mAb YTS177.9. Moreover, the activity of this nondepleting mAb was found to be dose-dependent and 80% of grafts survived permanently when the dose was increased to six injections of 0.5 mg mAb. Like mAb GK1.5, mAb YTS177.9 also prevented rejection when given after a delay of two days posttransplant. In addition, we found that neither depleting nor nondepleting anti-CD8 mAb was effective in this model. Our results strongly suggest that an anti-CD4 nondepleting or blocking mAb alone is able to induce long-term acceptance of islet xenografts and that blocking the CD4 molecule is significantly superior to depleting CD4 positive cells for the protection of islet xenografts. This may indicate that CD4 cells play a major role in xenograft tolerance induction.
Lu
X
X
Novartis Pharma, Inc., Transplantation Research, Basel, Switzerland.
Schulz
M
M
Zihlmann
H R
HR
Borel
J F
JF
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D015704:CD4 Antigens / Q000276:immunology*; D006224:Cricetinae; D003921:Diabetes Mellitus, Experimental / Q000276:immunology; D000939:Epitopes; D006085:Graft Survival / Q000276:immunology*; D006801:Humans; D066298:In Vitro Techniques; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D008647:Mesocricetus; D051379:Mice; D008808:Mice, Inbred CBA; D016176:T-Lymphocyte Subsets / Q000276:immunology; D014183:Transplantation, Heterologous / Q000276:immunology*
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D000939:Epitopes