Inhibitory effect of a CD4-CDR3 peptide analog on graft-versus-host disease across a major histocompatibility complex-haploidentical barrier.

Abstract

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.

• Authors: R M Townsend, C Briggs, J C Marini, G F Murphy, R Korngold
• Journal: Blood (Blood) Vol. 88 Issue 8 Pg. 3038-47 (Oct 15 1996) ISSN: 0006-4971 [Print] United States
• PMID: 8874202 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• CD4 Antigens
• Immunosuppressive Agents
• Oligopeptides
• Peptide Fragments
• reverse D amino acid mouse proline-glycine-proline peptide

Topics

• Acute Disease
• Amino Acid Sequence
• Animals
• Bone Marrow Transplantation (adverse effects)
• CD4 Antigens (chemistry)
• CD4-Positive T-Lymphocytes (drug effects, immunology)
• Drug Evaluation, Preclinical
• Graft vs Host Disease (drug therapy)
• Graft vs Host Reaction (drug effects)
• Haplotypes (genetics)
• Immunosuppressive Agents (pharmacology, therapeutic use)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Inbred DBA
• Molecular Sequence Data
• Oligopeptides (pharmacology, therapeutic use)
• Peptide Fragments (pharmacology, therapeutic use)
• Radiation Chimera