INHIBITORY EFFECT OF A CD4-CDR3 PEPTIDE ANALOG ON GRAFT-VERSUS-HOST DISEASE ACROSS A MAJOR HISTOCOMPATIBILITY COMPLEX-HAPLOIDENTICAL BARRIER

A structure-based designed peptide has been engineered to exhibit the same molecular surface as a portion of the CDR3-like region in domain 1 of the murine CD4 molecule. Earlier in vitro experiments indicated t hat this analog, known as rD-mPGPtide, inhibited T-cell proliferation in mixed lymphocyte reactions and blocked activation of both normal CD 4(+) T cells and T-cell lines after T-cell receptor triggering. In add ition, rD-mPGPtide proved to be a potent inhibitor in vivo of CD4(+) T -cell-mediated experimental allergic encephalomyelitis disease in the SJL mouse model. In this current report, we have evaluated the potenti al of rD-mPGPtide for suppressing the development of graft-versus-host disease (GVHD) in an irradiated major histocompatibility complex (MHC )-haploidentical murine bone marrow transplantation (BMT) model [(B6 x DBA/(2))F-1 --> (B6 x CBA)F-1 (950 cGy)]. Our results indicated that early administration of rD-mPGPtide was effective in the inhibition of alloreactive responses of the donor T cells against the host and thus delayed or prevented the onset of GVHD. The median survival time of a nimals treated with rD-mPGPtide was enhanced as much as four-fold with as little as a single dose of peptide at the time of transplant. Decr eased alloreactivity was indicated by phenotypic and functional analys is of positively selected thoracic duct lymphocytes 4 days after trans plant and by histopathological examination of skin and gastrointestina l tissue samples 4 weeks later. Therefore, the administration of a CD4 -CDR3 peptide is an efficacious approach against the development of GV HD during allogeneic BMT. (C) 1996 by The American Society of Hematolo gy.