Mechanisms of antigen presentation to T cells in murine graft-versus-host disease: cross-presentation and the appearance of cross-presentation.

Recipient antigen-presenting cells (APCs) initiate GVHD by directly presenting host minor histocompatibility antigens (miHAs) to donor CD8 cells. However, later after transplantation, host APCs are replaced by donor APCs, and if pathogenic CD8 cells continue to require APC stimulation, then donor APCs must cross-present host miHAs. Consistent with this, CD8-mediated GVHD is reduced when donor APCs are MHC class I(-). To study cross-presentation, we used hosts that express defined MHC class I K(b)-restricted miHAs, crossed to K(b)-deficient backgrounds, such that these antigens cannot be directly presented. Cross-priming was surprisingly efficient, whether antigen was restricted to the hematopoietic or nonhematopoietic compartments. Cross-primed CD8 cells were cytolytic and produced IFN-γ. CD8 cells were exclusively primed by donor CD11c(+) cells, and optimal cross-priming required that they are stimulated by both type I IFNs and CD40L. In studying which donor APCs acquire host miHAs, we made the surprising discovery that there was a large-scale transfer of transmembrane proteins from irradiated hosts, including MHC class I-peptide complexes, to donor cells, including dendritic cells. Donor dendritic cells that acquired host MHC class I-peptide complexes were potent stimulators of peptide-specific T cells. These studies identify new therapeutic targets for GVHD treatment and a novel mechanism whereby donor APCs prime host-reactive T cells.

Development of anti-major histocompatibility complex class I or II antibodies following left ventricular assist device implantation: effects on subsequent allograft rejection and survival.

BACKGROUND: Previous reports have indicated that antibodies to HLA class I or II antigens develop in approximately 60% of patients following left ventricular assist device (LVAD) implantation, subsequent rates of allograft rejection are higher, and survival is adversely affected. METHODS: We performed an analysis of the incidence of antibody development to HLA class I or II antigens by panel reactive antibody (PRA) screening following implantation of the HeartMate LVAD in 38 patients from October 1, 1996 to March 1, 2000 (6 LVAD deaths excluded from study). The occurrence of vascular or cellular rejection of International Society of Heart and Lung Transplantation grade > or = 3A, as determined by endomyocardial biopsy following heart transplantation (HTX), were compared for patients with (n = 32, LVAD group) or without (n = 68, control group) preoperative LVAD support. RESULTS: After LVAD implantation, 9 patients (28%) in the LVAD group developed IgG antibodies to class I (n = 3), class II (n = 5), or both antigens (n = 1) with PRA > 10%. The remaining 23 patients (72%) had either no detectable IgG antibody development or IgG antibody development with PRA < 10%. At the time of HTX, only 4 patients in the LVAD group had persistent PRA > 10%. Only 3 patients (4%) in the control group had PRA > 10% at the time of HTX. The incidence of patients free from rejection at 6 and 12 months was 62% and 44% for the control group, and 49%, and 40% for the LVAD group, respectively (p not significant). The mean linearized rate plus or minus standard deviation of allograft rejection from 0 to 6 months and 7 to 12 months was 0.13 +/- 0.21 and 0.09 +/- 0.14 episodes a month, respectively, for patients with no LVAD support, and 0.17 +/-.25 and 0.06 +/- 0.1 episodes a month, respectively, for those with LVAD support (p = not significant). Post-transplantation survival at 1 and 2 years was 90% and 90%, respectively, for the control group, and 97% and 92%, respectively, for the LVAD group (p not significant). CONCLUSION: Patients with LVAD support before HTX do not appear to be at increased risk for significant allograft rejection in the first year or for death within the first 2 years after transplantation.

Decreased cytotoxic activity of natural killer cells in kidney allograft recipients treated with human HLA-derived peptide.

Peptides derived from a conserved region (aa 75-84) of HLA class I, overlapping the supertypic HLA-BW4/BW6 antigen region, have been shown to exhibit nonallele restricted immunosuppressive properties in rats and mice, prolonging survival of major histocompatibility complex-mismatched allografts. Furthermore, HLA-B7 peptides inhibit alloreactive cytotoxic cells, and both HLA-B7 and HLA-B2702 peptides inhibit natural killer (NK) cytotoxicity in vivo. In this article, we report on a randomized, controlled study of the safety and pharmacokinetics of HLA-B2702-derived peptide in human recipients of a first kidney allograft. Escalating doses of HLA-B2702 were compared with doses of placebo controls. No toxicity and no immunization against the peptide were noted. Although the study was not designed as an efficacy trial, patients who received the high-dose protocol (7 mg/kg) did experience more rejection episodes, but this was not statistically significant when compared with control patients. Interestingly, in human recipients, as previously observed in rodents, administration of the peptide was associated with a statistically significant decrease in the cytotoxicity of NK cells against K562 targets (P<0.001). As these peptides correspond to a region of the HLA class I molecule that interacts with the newly described NK receptors for class I, their mode of action through interaction with such receptors is discussed. As a peptide of the same sequence from HLA-B7 blocks both NK and alloreactive T cell cytotoxicity, it is possible that, in humans too, both types of cytotoxic cells are affected by this peptide. The biological significance of these observations should be confirmed in future controlled studies with a larger patient population.