Development and regulation of alloantibody responses following cardiac allograft transplantation.

The in vivo generation of cytotoxic alloantibody was examined following cardiac allograft transplantation. C57BL/ mice were transplanted with DBA/2 hearts, and sera were collected at different time points after transplantation. A kinetic study revealed that donor-specific cytotoxic antibody production was bimodal. Antibody was detectable by day 3 after heart transplantation and peaked at day 7. It was associated with activated helper T lymphocytes (HTL) as determined by limiting Dilution Analysis (LDA). The alloantibody titer declined by day 14, followed by a second peak at day 21. The early peak at day 7 was mainly composed of IgM, but the later peak contained predominately IgG. To determine the role of T cells in the production of the alloantibody, the recipients were treated with anti-CD4 mAb GK1.5 or anti-CD8 mAB 19-178 to deplete CD4 T cells or CD8 T cells, respectively. They were also treated with cyclosporine A (CsA) to inhibit general T cell activation. Following anti-CD4 mAb or CsA treatment, the HTL responses were reduced and the alloantibody responses were lowered. These antibody responses found in the absence of activated HTL were transient without isotype switching from IgM to IgG. In contrast, anti-CD8 mAB treatment had no inhibitory effect on the development of alloantibody. These data suggest tat the donor-specific alloantibody response was mainly T cell-dependent. Alloantibody development required activated helper T cells. However, a transient T cell-dependent antibody response was observed at an early stage in the rejection process.