Nicole Suciu-Foca, PhD

Allograft rejection is a complex phenomenon which involves both the cellular and humoral arm of the immune response. This process is triggered by disparate histocompatibility antigens expressed by graft tissue and recognized by recipient T and B lymphocytes. There are two pathways by which T cells may recognize MHC alloantigens. The direct pathway involves T cell recognition of intact MHC molecules expressed by donor APC. The second, or indirect, pathway describes T cell recognition of peptides derived from the processing and presentation of allogeneic MHC molecules on self antigen-presenting cells.

Studies performed in our laboratory have demonstrated the crucial role of indirect alloreactivity in both acute and chronic rejection of human organ allografts. We showed that rejection is initiated by a clonal population of T cells, which recognize a unique immunodominant peptide derived from the hypervariable region of a donor HLA-DR molecule. We have demonstrated that immunodominant peptides can be used for early diagnosis and suppression of T cell alloreactivity. However, during recurring episodes of acute rejection as well as at the onset of chronic rejection intra and intermolecular spreading of T cell epitopes occurs. T cells recognizing cryptic epitopes of the same molecule or determinants of another mismatched HLA-DR antigen become activated, contributing to the amplification and perpetuation of the immune response (Figure 1). Using techniques of protein chemistry, molecular biology and cellular immunology we are engineering "peptide vaccines" which suppress the reactivity of alloimmune T cells against the specific target.

More recently we have described the functional and phenotypic characteristics of a subset of T lymphocytes with suppressor function. T suppressor cells express the CD3+CD8+CD28- phenotype, use a restricted repertoire of TCR Vb genes and recognize peptides presented by MHC class I molecules. These CD8+CD28- T cells suppress the activation of CD4+ T helper cells by down-regulating the expression of costimulatory molecules CD40, CD80 and CD86 on antigen presenting cells (Figure 2). We are investigating the molecular mechanism of suppression and the possibility of inhibiting the direct and indirect pathway by induction and/or adoptive transfer of suppression.

Selected Publications:

• Liu, Z., Colovai, A.I., Tugulea, S., Reed, E.F., Fisher, P.E., Mancini, D., Rose, E.A., Cortesini, R., Michler, R.E., and Suciu-Foca, N. Indirect recognition of donor HLA-DR peptides in organ allograft rejection. J. Clin. Invest. 98: 1150-1157 (1996).

• Colovai, A.I., Liu, Z., Harris, P.E., Cortesini, R., and Suciu-Foca, N. Allopeptide-specific T cell reactivity altered by peptide analogs. J. Immunol. 158: 48-54 (1997).

• Ciubotariu, R., Liu, Z., Colovai, A.I., Ho, E., Ravalli, S., Itescu, S., Hardy, M.A., Cortisini, R., Rose, E.A, and Suciu-Foca, N. Persistent allopeptide reactivity and epitope spreading in chronic rejection of organ allografts. J. Clin. Invest. 101: 398-405 (1998).

• Liu, Z., Tugulea, S., Cortesini, R., and Suciu-Foca, N. Specific suppression of T helper alloreactivity by allo-MHC-class I restricted CD8+ CD28- T cells. International Immunology. 10: 101-109 (1998).

• Ciubotariu, R., Colovai, A.I., Pennesi, G., Lui, Z., Smith, D., Berlocco, P., Cortesini, R., and Suciu-Foca, N. Specific suppression of human CD4+ T helper cell responses to pig MHC antigens by CD8+CD28-regulatory T cells. J. Immunology (in press, Nov. 1998).

• Jiang, S., Tugulea, S., Pennesi, G., Liu, Z., Mulder, A., Harris, P., Cortesini, R., and Suciu-Foca, N. Induction of MHC-class I restricted human suppressor T cells by peptide priming in vitro. Human Immunology. 59: 11 (1998).