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Administration of a CD31-derived peptide delays the onset and significantly increases survival from lethal
1Department of Medicine, Stanford University Medical Center, CA 94305, USA.
Abstract:
The CD31 monoclonal antibody, LYP21, binds to the CD31 domain 6 and inhibits the human mixed-lymphocyte reaction (MLR) in a specific and dose-dependent fashion. A synthetic CD31 peptide based on human CD31 epitope (amino acids 551 to 574) recognized by LYP21 is equally effective in inhibiting the MLR. In this study, we used the murine homolog of CD31 peptide 551 to 574 and a control peptide to study the role of CD31 molecule on T-cell activation. In vitro, CD31 peptide inhibited the MLR across several major and minor histocompatibility differences in a specific and dose-dependent fashion, similar to the results observed in the human system. Maximal inhibition was achieved at a dose of 200 microg/mL. In the cytotoxic T-lymphocyte (CTL) assay, CD31 peptide inhibited CTL responses by 97%. To study the in vivo effect of this peptide, graft-versus-host disease (GVHD) across minor histocompatibility barriers was induced in the B10.D2 (H-2d) --> BALB/c (H-2d) model. BALB/c recipients received CD31 peptide (100 microg/d), or phosphate-buffered saline (PBS), or control peptide (100 microg/d) intraperitoneally (IP) for the first 5 weeks. CD31 peptide delayed onset of graft-versus-host disease and significantly increased long-term survival. Twelve of 14 mice receiving CD31 peptide survived more than 100 days after transplantation, as compared with none of 10 mice receiving PBS and none of five mice receiving control peptide (P = .0001). Long-term engraftment of allogeneic bone marrow was documented in all transplanted mice by polymerase chain reaction (PCR) analysis of microsatellite region in the interleukin (IL)-1beta gene. Our data suggest that the CD31 molecule has an important functional role in T-cell activation in vitro and in vivo.
Insights
A synthetic CD31 peptide effectively inhibits T-cell activation and mixed-lymphocyte reactions in vitro and in vivo. This peptide significantly delays graft-versus-host disease and improves long-term survival in transplantation models.
Area of Science:
- Immunology
- Molecular Biology
- Transplantation Science
Background:
- CD31 is a molecule involved in T-cell activation.
- A CD31 monoclonal antibody (LYP21) and a synthetic peptide targeting CD31 inhibit human mixed-lymphocyte reactions (MLR).
Purpose of the Study:
- To investigate the role of the CD31 molecule in T-cell activation using a murine CD31 peptide.
- To evaluate the in vitro and in vivo efficacy of a CD31 peptide in modulating immune responses.
Main Methods:
- In vitro studies included mixed-lymphocyte reactions (MLR) and cytotoxic T-lymphocyte (CTL) assays using a murine CD31 peptide.
- In vivo studies utilized a murine model of graft-versus-host disease (GVHD) induced across minor histocompatibility barriers.
- Mice received CD31 peptide, control peptide, or phosphate-buffered saline (PBS) intraperitoneally.
Main Results:
- The CD31 peptide demonstrated specific, dose-dependent inhibition of MLR in vitro, similar to human studies.
- The peptide achieved maximal MLR inhibition at 200 microg/mL and inhibited CTL responses by 97%.
- In vivo, CD31 peptide treatment delayed GVHD onset and significantly increased long-term survival (12/14 mice survived >100 days) compared to controls (P = .0001).
Conclusions:
- The CD31 molecule plays a critical role in T-cell activation.
- The synthetic CD31 peptide is a potent inhibitor of T-cell mediated immune responses.
- CD31 peptide therapy shows promise for mitigating GVHD and improving outcomes in allogeneic transplantation.