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A synthetic CD4-CDR3 peptide analog enhances bone marrow engraftment across
major histocompatibility barriers
U Koch and R Korngold
Kimmel Cancer Institute, Jefferson Medical College, Philadelphia, PA 19107,
USA.
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.
Volume 89,
Issue 8,
pp. 2880-2890,
04/15/1997
Copyright © 1997 by The American Society of Hematology
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