Combination therapy with a CD4-CDR3 peptide analog and cyclosporin A to prevent graft-vs-host disease in a MHC-haploidentical bone marrow transplantation model.
Graft-versus-host disease (GVHD) is a major complication associated with allogeneic bone marrow transplantation (BMT). Cyclosporin A (CsA) has been used as the basis for most immunosuppressive regimens for the prevention of GVHD, but has exhibited only limited effects and is hampered by nephrotoxicity, neurotoxicity, and hepatotoxicity. Previously, we showed that rD-mPGPtide, a structure-base designed peptide analog of the CDR3-like region of domain 1 of the murine CD4 molecule, suppressed the development of GVHD in a MHC-haploidentical murine BMT model when administered early in the course of disease. This peptide analog also inhibited T cell proliferation in mixed lymphocyte reactions (MLR) in vitro. The current results demonstrate that CsA and rD-mPGPtide exhibit an additive inhibitory effect on MLR. Furthermore, the use of CsA and rD-mPGPtide together for prevention of GVHD nearly doubled the median survival time of the mice compared to either agent alone. In addition, the combination therapy reduced the requirement for habitual administration of CsA. Therefore, the use of a CD4-CDR3 peptide can complement and potentiate the immunosuppressive effects of CsA in the prevention of GVHD following allogeneic BMT.
Townsend
R M
RM
Kimmel Cancer Institute, Jefferson Medical College, Philadelphia, Pennsylvania 19107, USA.
Gilbert
M J
MJ
Korngold
R
R
D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects*; D016572:Cyclosporine / Q000008:administration & dosage / Q000627:therapeutic use*; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006086:Graft vs Host Disease / Q000209:etiology / Q000517:prevention & control*; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D051379:Mice; D009842:Oligopeptides / Q000627:therapeutic use*; D014184:Transplantation, Homologous / Q000009:adverse effects*
D007166:Immunosuppressive Agents; D009842:Oligopeptides; C101909:reverse D amino acid mouse proline-glycine-proline peptide; D016572:Cyclosporine