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 that this analog, known as rD-mPGPtide, inhibited T-cell proliferation in mixed lymphocyte reactions and blocked activation of both normal CD4+ T cells and T-cell lines after T-cell receptor triggering. In addition, 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 potential 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)F1-->(B6 x CBA)F1 (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 animals 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. Decreased alloreactivity was indicated by phenotypic and functional analysis of positively selected thoracic duct lymphocytes 4 days after transplant and by histopathological examination of skin and gastrointestinal tissue samples 4 weeks later. Therefore, the administration of a CD4-CDR3 peptide is an efficacious approach against the development of GVHD during allogeneic BMT.
Townsend
R M
RM
Kimmel Cancer Institute, Jefferson Medical College, Philadelphia, PA 19107, USA.
Briggs
C
C
Marini
J C
JC
Murphy
G F
GF
Korngold
R
R
D000208:Acute Disease; D000595:Amino Acid Sequence; D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects*; D015704:CD4 Antigens / Q000737:chemistry*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D004353:Drug Evaluation, Preclinical; D006086:Graft vs Host Disease / Q000188:drug therapy*; D006087:Graft vs Host Reaction / Q000187:drug effects; D006239:Haplotypes / Q000235:genetics; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000494:pharmacology / Q000627:therapeutic use*; D011828:Radiation Chimera
D015704:CD4 Antigens; D007166:Immunosuppressive Agents; D009842:Oligopeptides; D010446:Peptide Fragments; C101909:reverse D amino acid mouse proline-glycine-proline peptide