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The mfluence of HLA mismatches between donor and recipient on the phenotypes, function, and specificity of T-lymphocyte cultures derived from endomyocardial biopsies was studied in 118 heart transplant recipients In case of HLA-DR mismatches, the malorlty of the EMB-derived cultures were dommated by CD4 ÷ T cells while, in patients with HLA-A and -B mismatches but without DR mismatches, CD8 ÷ T cells comprised the predommant T-cell subset Cytotoxiclty against donor antigens was observed in 75% of the cultures A significantly (p < 0 005) lower proportion of the cultures showed cytotoxiclty against HLA-A antigens (36%) when compared with HLA-B (53%) or HLA-DR (49%) An HLA-A2 mismatch elicited a cytotoxlc response that was comparable to that found against HLA-B and -DR antigens 62% of the cultures from HLA-A2 mismatched donor-rec,plent combinations was reactive against A2 A higher number of A, B, or DR mismatches resulted m a higher number of cytotoxlc cultures directed against these antigens A higher number of HLA-B and -DR mismatches was associated with a lower freedom from relection Our data indicate that, despite the use of adequate immunosuppresslve therapy, the degree of HLA matchIng plays a crucial role in the immune response agamst a transplanted heart, resulting m a s,gmficant effect on freedom from re}ection Human Immunology 39, 233-242 (1994

From 535 endomyocardial biopsies (87 heart transplant recipients) 283 cell cultures could be generated. All cultures tested contained T lymphocytes and in most cases CD4 was the predominant phenotype at any time posttransplant. A significantly higher proportion of CD8-dominated cultures was found among cultures from biopsies without myocytolysis. In the first 3 months post transplant 57% of cultures showed cytotoxicity against both class I and class II mismatched donor major histocompatibility complex (MHC) antigens, changing to an incidence of 33% at greater than 90 days. This proved to be due to a significant decrease in the number of cultures with human leukocyte antigen class II-directed cytotoxicity. This study shows that early after transplantation a heart transplant is infiltrated with activated donor-specific cytotoxic T cells which recognize a broad spectrum of mismatched donor MHC antigens, and that in time this spectrum becomes more restricted.

We have investigated whether cytomegalovirus (CMV) infection has an effect on donor directed cytotoxicity of graft-infiltrating cells in human heart transplants. Our study group consisted of 89 heart transplant recipients. Thirty-eight (43%) showed signs of CMV infection; in 28 of them, cytolytic activity of biopsy derived cultures could be tested during the infection. Eight patients had a primary and 20 a secondary infection. We found that during CMV infection, both primary and secondary, a significantly higher proportion of the biopsy-derived cultures showed cytotoxicity against donor HLA antigens (chi 2 test; P < 0.01 in comparison with 51 patients without infection). This was most evident in patients with both infection and acute rejection episodes when compared to patients with only one of these complications. This suggests that one process amplifies the other with regard to the up-regulation of alloreactivity within the transplanted heart. In secondary infections, only an increase of donor class I-directed cytotoxicity was found, while in primary infections cytotoxicity against donor class I and II antigens was increased (P < 0.005 vs. secondary infection).

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