A synthetic CD4-CDR3 peptide analog enhances bone marrow engraftment across major histocompatibility barriers.
The efficacy of a synthetic peptide analog mimicking the CDR3-D1 domain of the CD4 molecule was investigated in murine models of allogeneic bone marrow engraftment after transplantation across major histocompatibility complex (MHC) barriers. A single dose of a CD4-CDR3 peptide analog was administered at the time of marrow transplantation to three different allogeneic mouse strain combinations after appropriate sublethal total body irradiation: (1) B10.BR --> C57BL/6J (B6), a full allogeneic MHC difference; (2) (B6xDBA/2)F1 --> (B6xCBA)F1, a haploidentical MHC combination; and (3) B6.C-H2bm12 --> B6-Ly5.2, involving only a MHC class II difference. Donor-host chimerism was assessed after 1 and 2 months posttransplantation by flow cytometric analysis of spleen and/or lymph node cells. Peptide-treated animals in all three strain combinations exhibited significantly enhanced donor lymphoid engraftment, which was similarly reflected in the total lymphocyte compartment and its T-cell (CD4+, CD8+) and B-cell subsets. In addition, peptide-treated mice in the haploidentical and MHC class II-mismatched strain combinations exhibited prolonged tolerance of both donor and syngeneic host-type tail skin grafts while rejecting third-party allogeneic grafts, thus supporting the reconstitution of immunocompetence in these chimeras. Lymphocytes from the peptide-treated haploidentical chimeric mice also displayed donor-specific tolerance upon stimulation in a one-way mixed lymphocyte reaction. In a 6-day colony-forming unit-granulocyte-macrophage (CFU-GM) assay to quantitate the level of hematopoietic cell engraftment in both the haploidentical and class II-disparate strain combinations, bone marrow cells from the peptide-treated mice exhibited significant increases in CFU-GM compared with the saline-treated control groups. Finally, early multiple treatments with the peptide after transplantation significantly enhanced donor chimerism in donor-presensitized recipient mice across the MHC class II barrier and proved to be significantly more effective than anti-CD4 monoclonal antibody treatment. These results indicate that the structure-based CD4-CDR3 peptide analog may represent a valuable approach to the inhibition of graft rejection after MHC-mismatched bone marrow transplantation.
Koch
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U
Kimmel Cancer Institute, Jefferson Medical College, Philadelphia, PA 19107, USA.
Korngold
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R
D000818:Animals; D001803:Blood Transfusion; D016026:Bone Marrow Transplantation / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003433:Crosses, Genetic; D005260:Female; D006082:Graft Enhancement, Immunologic; D006085:Graft Survival / Q000187:drug effects; D006183:H-2 Antigens / Q000276:immunology*; D006410:Hematopoiesis; D007108:Immune Tolerance; D007121:Immunocompetence; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008811:Mice, Inbred DBA; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use*; D011828:Radiation Chimera; D013329:Structure-Activity Relationship; D014184:Transplantation, Homologous / Q000276:immunology
D006183:H-2 Antigens; D009842:Oligopeptides; C101909:reverse D amino acid mouse proline-glycine-proline peptide