Monoclonal antibodies as tools to induce immune tolerance

Abstract

The induction of donor specific transplantation tolerance remains the ultimate goal for clinical organ grafting, as it would avoid the problems of toxicity, susceptibility to infections and tumors that arise from the current need to give long-term, nonspecific, immunosuppressive drugs. It is now more than 50 years since it was first demonstrated that such tolerance could be induced in neonatal rodents, or lethally irradiated adults, by inducing sufficient donor chimerism to maintain tolerance by clonal deletion of alloreactive T cells in the thymus. Many different attempts to extend such approaches to the clinic have generally not proven to be viable. More recently, it was found that monoclonal antibodies against various T-cell antigens, particularly combinations of CD4, CD40L, and CD8, were able to block rejection of allografts in adult rodents [1]. More important, such recipients eventually became specifically tolerant of the donor alloantigens, able to accept fresh donor-type grafts, but reject those from a third party. This induction of tolerance did not require any depletion or overt clonal deletion of donor-reactive T cells, and was independent of the thymus. Tolerance could be induced directly to skin [1] or vascularized heart grafts [2] across a full major histocompatibility complex (MHC) plus minor antigens mismatch. In vitro there were no differences in T-cell responses from tolerant or rejecting mice, but tolerance in vivo was found to be dependent on CD4 + regulatory T cells [3].