Immunosuppression by D-isomers of HLA class I heavy chain (amino acid 75 to 84)-derived peptides is independent of binding to HSC70.
BACKGROUND
Peptides derived from the class I heavy chain were shown to modulate immune responses in vitro and in vivo. A peptide derived from HLA-B2702 (2702.75-84) inhibited differentiation of cytotoxic T cells as well as T cell and natural killer cell-mediated cytotoxicity in vitro. Peptide-mediated immunomodulation seemed to be independent of the MHC proteins expressed by responder and stimulator cells. In vivo studies in rodents demonstrated prolongation of heart and skin allograft survival after peptide therapy. Here, the correlation between the peptide's biological activity and its amino acid sequence was analyzed using peptides derived from amino acid 75-84 of several mouse, rat, and human MHC class I proteins as well as peptides with single amino acid substitutions in the 2702.75-84 sequence.


METHODS
Peptides consisting of both L- and D-amino acids were tested for inhibition of murine and human T cell-mediated and lymphokine-activated killer cell-mediated cytotoxicity, binding to hsc70, and prolongation of heart allograft survival in vivo.


RESULTS
Replacement of glutamic acid residue (E) at position 75 with valine (V) resulted in a peptide [2702.75-84(E>V)] with increased in vitro and in vivo activity but unchanged affinity for hsc70. Surprisingly, both L- and D-isomers of 2702.75-84 and 2702.75-84(E>V) inhibited cytotoxic cells in vitro and prolonged heart allograft survival in vivo. However, as expected, the peptides consisting of D-amino acids did not bind to hsc70.


CONCLUSIONS
Assuming that both D- and L-isomers modulate immune responses by similar mechanisms, these results suggest that the peptides' effect is independent of binding to hsc70.
Woo
J
J
SangStat Medical Corporation, Menlo Park, California 94025, USA.
Iyer
S
S
Cornejo
M C
MC
Gao
L
L
Cuturi
C
C
Soulillou
J P
JP
Buelow
R
R
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000595:Amino Acid Sequence; D000818:Animals; D002846:Chromatography, Affinity; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D019281:Dimerization; D006085:Graft Survival / Q000276:immunology; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D016027:Heart Transplantation / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000737:chemistry*; D006801:Humans; D015979:Killer Cells, Lymphokine-Activated / Q000187:drug effects; D010455:Peptides / Q000276:immunology*; D011485:Protein Binding / Q000187:drug effects; D013237:Stereoisomerism
D000276:Adjuvants, Immunologic; D018840:HSP70 Heat-Shock Proteins; D015395:Histocompatibility Antigens Class I; D010455:Peptides; C092373:allotrap; D000251:Adenosine Triphosphatases