Definition of agonists and design of antagonists for alloreactive T cell clones using synthetic peptide libraries

Alloreactive T cells form an important barrier for organ transplantation. T o reduce the risk of rejection patients are given immunosuppressive drugs, which increase the chance of infection and the incidence of malignancies. I t has been shown that a large proportion of alloreactive T cells specifical ly recognize peptides present in the groove of the allogeneic MHC molecule. This implies that it might be possible to modulate the alloresponse by pep tides with antagonistic properties, thus preventing rejection without the s ide effects of general immunosuppression, Peptide antagonists can be design ed on the basis of the original agonist, yet for alloreactive T cells these agonists are usually unknown. In this study we have used a dedicated synth etic peptide library to identify agonists for HLA-DR3-specific alloreactive T cell clones. Based on these agonists, altered peptide ligands (APL) were designed, Three APL could antagonize an alloreactive T cell clone in its r esponse against the library-derived agonist as well as in its response agai nst the original allodeterminant, HLA-DRS. This demonstrates that peptide l ibraries can be used to design antagonists for alloreactive T cells without knowledge about the nature of the actual allostimulatory peptide. Since th e most potent agonists are selected, this strategy permits detection of pot ent antagonists. The results, however, also suggest that the degree of pept ide dependency of alloreactive T cell clones may dictate whether a peptide antagonist can be found for such clones. Whether peptide antagonists will b e valuable in the development of donor-patient-specific immunosuppression m ay therefore depend on the specificity of the in vivo-generated alloreactiv e T cells.