Prospects for anti-rejection therapies based upon CD8-dependent immunoregulation

In this article we propose that anti-rejection immunotherapies for countering acute allograft rejection can be designed around manipulation of the cell surface phenotype of alloantigen-presenting cells (allo-APCs) in ways that convert them from T cell activators to inhibitors. It is further suggested that a class of molecules, termed "coinhibitors," can be defined that carry out this APC conversion process. Data are summarized indicating that the human lymphoid cell surface molecule CD8 has such a trans-coinhibitor function which is in addition to the cis-coreceptor and adhesin functions traditionally ascribed to it. Antisense and sense gene transfer studies indicate that CD8 on the surface of allo-APCs leads to inhibition of allospecific T cell responders. We have explored the possibility of using protein, rather than gene, transfer as a therapeutic strategy for delivering CD8 to APC surfaces. Two membrane-binding variants of CD8 have been assembled to show retention of the coinhibitor function of native CD8. Immunotherapeutic possibilities associated with these chimeric CD8 polypeptides in the clinical context of renal and other organ transplantation are considered.