Mechanism of liver allograft rejection: the indirect recognition pathway.

Transplant rejection is mediated by the direct and indirect pathways. To explore the role of the indirect recognition pathway in the rejection of liver allografts, T cells obtained from peripheral blood were expanded in medium containing IL-2 and tested in LDA for reactivity to synthetic peptides corresponding to the hypervariable regions of the mismatched HLA-DR antigen(s) of the donor. Serial investigations of 17 recipients showed that T-cell reactivity to donor HLA-DR peptides was strongly associated with acute rejection episodes. In recipients carrying a graft that was mismatched by two HLA-DR alleles, a single donor antigen was targeted during primary rejection, although allopeptide reactivity against the second HLA-DR antigen was observed during subsequent episodes of acute rejection. The finding that allopeptide reactivity occurs early following transplantation and is predictive of rejection is consistent with the notion that processing of donor alloantigens by recipient APCs activates the indirect T-cell recognition pathway that plays a major role in initiating and amplifying allograft rejection.

New approaches to specific immunomodulation in transplantation.

T cells can recognize foreign MHC antigens by two distinct routes, either directly as intact molecules, or indirectly as processed peptides. Recent evidence strongly suggests that the indirect pathway of allorecognition plays a key role in initiating and sustaining graft rejection. Theoretically, all mismatched HLA alloantigens could generate immunogenic peptides which may be recognized in the context of any of the two self HLA-DR molecules. However, indirect recognition appears to be limited to a single peptide determinant of an allogeneic HLA-DR molecule and restricted by one self HLA-DR molecule. Furthermore, T cells involved in the self-restricted allopeptide recognition express a limited array of T cell receptor variable genes. These findings suggest that selective immune interventions, such as peptide blockade of the self HLA-DR molecule involved in the presentation of the dominant allopeptide, induction of high-zone tolerance or TCR antagonism, may be devised to prevent graft rejection.

Homing of CD4+CD56+ T lymphocytes into kidney allografts during tubular necrosis or rejection.

The association between acute rejection, acute tubular necrosis, good function and relative infiltration of CD56 subsets of both CD8+ and CD4+ T cells was examined on 67 samples of graft infiltrating cells (GIC) and corresponding peripheral blood lymphocytes (PBL) obtained from renal allograft recipients. Quantification of cell subset profiles was determined by two-color flow cytometry. While a high proportion of CD4+CD56+ GIC was detected when both renal dysfunction and graft cytopathology (acute tubular necrosis or acute rejection) were present, this cell subset was undetectable in peripheral blood. In contrast the CD8+CD56+ T-cell subset was not discriminatory. The presence of CD4+CD56+ cells among freshly-isolated lymphocytes from renal allografts supports the idea that the local environment is involved in the selection of this subset, thus participating in the amplification of the immune-response. In addition, a homing of this T-cell subset into the transplanted organ may constitute an early sign of graft immunopathology.

Enhanced production of interferon-gamma by T lymphocytes cloned from rejected kidney grafts.

Seventy-seven T cell clones were generated from cell blasts infiltrating rejected kidney allografts. All clones, either CD4 or CD8, displayed cytolytic activity evaluated by lectin-dependent cell-mediated cytotoxicity (LDCC) and natural killer activities. Furthermore, both types of clones were able to produce IFN-gamma following PHA stimulation. These data suggest that the graft infiltrate is characterized by T cell clones with cytolytic potential responsible for the killing of graft cells. The production of IFN-gamma, enhancing the class II MHC expression, may amplify the recipient immune response.

Effect of cyclosporin A on natural killer cells' response during viral infections.

In the this study the modification of lymphocyte subsets (T3, T4, T8) and Natural Killer (NK) cells in organ transplanted patients treated with Cyclosporin A (CyA) in the course of viral infection, have been analyzed. Different subsets have been studied with the monoclonal antibody method and infective processes have been verified by serological data of seroconversion. Our study has shown that CyA at the adopted doses does not alter NK response to viral infection; in fact, in patients with seroconversion, higher NK values and lower OKT4/OKT8 ratio values have been found with respect to patients who did not show any viral infection serologic data. Furthermore an increased incidence of reject crisis has been observed in patients with seroconversion.