Peptide analogues as a strategy to induce tolerance in T cells with indirect allospecificity.
BACKGROUND
It has been demonstrated that indirect recognition of allogeneic MHC molecules might play an important role in provoking graft rejection. Although direct recognition of allogeneic molecules on antigen presenting cells of the graft may induce a state of tolerance, the continuous presentation of processed alloantigens by specialized antigen presenting cells does not allow the same phenomenon to occur. Tolerance to interleukin-2 secreting T cells can be achieved in different ways, among these is the exposure to mutants of the wild type allopeptide. We have investigated whether peptide analogues of the allopeptide can induce tolerance in T cells with indirect allospecificity.


METHODS
T cell clones with indirect anti-HLA-A2-specificity generated from a HLA-A2-DRB1*1502+ patient who chronically rejected a HLA-A2-expressing kidney allograft were used for this study. Nine peptide analogues of HLA-A2 (residues: 103-120) were produced with single amino acid substitutions at the putative T cell receptor for antigen contact positions. Their effect on the proliferation of a panel of T cell clones was evaluated.


RESULTS
Peptide analogues and wild type peptide had similar capacity to bind to the restriction molecule HLA-DRB1*1502. Co-presentation of the peptide analogues 111R/A, H, K and 114H/K, with the wild type peptide inhibited T cell responses, indicative of antagonism. In addition, one analogue 112G/S induced unresponsiveness in the T cells to subsequent culture with the wild type peptide.


CONCLUSIONS
The data presented here suggest that using reagents such as altered peptides may represent a strategy to prevent the activation of T cells with indirect alloreactivity and allograft rejection in vivo.
Frasca
L
L
Department of Cell Development and Biology, La Sapienza University, Rome, Italy. lfrasca@axcasp.caspur.it
Tamir
A
A
Jurcevic
S
S
Marinari
B
B
Monizio
A
A
Sorrentino
R
R
Carbonari
M
M
Piccolella
E
E
Lechler
R I
RI
Lombardi
G
G
D000595:Amino Acid Sequence; D002460:Cell Line; D006084:Graft Rejection / Q000276:immunology; D015789:HLA-A2 Antigen / Q000276:immunology*; D006684:HLA-DR Antigens / Q000276:immunology; D059811:HLA-DRB1 Chains; D006801:Humans; D007165:Immunosuppression Therapy; D007376:Interleukin-2 / Q000276:immunology; D007519:Isoantigens / Q000276:immunology*; D016030:Kidney Transplantation / Q000276:immunology*; D008213:Lymphocyte Activation; D008285:Major Histocompatibility Complex; D008969:Molecular Sequence Data; D010455:Peptides / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D014184:Transplantation, Homologous
D015789:HLA-A2 Antigen; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D007376:Interleukin-2; D007519:Isoantigens; D010455:Peptides; D011948:Receptors, Antigen, T-Cell