Indefinite survival of neural xenografts induced with anti-CD4 monoclonal antibodies

Xenografts of neural tissue are usually rapidly rejected when transplanted into the central nervous system of adult recipient animals. This study has examined the cell mediated immune response to both concordant (between closely related species) and discordant (between distantly related species) neural xenografts in the mouse, and has investigated the role of the CD4(+) and CD8(+) T lymphocyte subsets in this process using monoclonal antibodies specific for the CD4 and CD8 cell surface glycoproteins. We have established that: (1) in this model system concordant neural xenograft rejection occurs within 15-30 days; however, xenograft survival can be dramatically prolonged with CD4(+), but not CD8(+), T lymphocyte depletion; (2) the administration of two successive courses of a high dose of anti-CD4 monoclonal antibody treatment results in indefinite concordant neural xenograft survival; (3) the mechanism by which the high dose anti-CD4 monoclonal antibody therapy appears to function involves the depletion of intrathymic CD4(+) cells; (4) anti-CD4 monoclonal antibody treatment enhances discordant neural xenograft survival, to beyond 60 days in many cases. These results demonstrate that CD4(+) T lymphocytes are of central importance in the immune response to both concordant and discordant neural xenoantigens. Thus the use of anti-CD4 monoclonal antibody therapy is an effective strategy to prolong significantly the survival of xenogeneic neural transplants. Furthermore this treatment caused no obvious deleterious side-effects. These findings have implications for future cross-species studies in experimental neurobiology and, possibly, in clinical neural transplantation.