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The proinflammatory cytokine tumor necrosis factor-? (TNF-?) is strongly implicated in graft-versus-host disease (GVHD) and other acute bone marrow transplant (BMT) complications. The antiinflammatory interleukin-10 (IL-10) antagonizes TNF-? and reduces GVHD. We previously showed association of recipient TNF (TNFd) and IL-10 (IL-10-1064) gene polymorphisms with acute GVHD severity in matched sibling BMT using only cyclosporin A monotherapy. The current study tested association of GVHD with TNFd and IL-10-1064/-1082 polymorphisms in a large cohort (144 matched sibling donor/recipient pairs) given both cyclosporine A (CyA) and methotrexate (MTX) prophylaxis. Genotype results were correlated with acute and chronic GVHD and mortality. Patients homozygous for the TNFd microsatellite allele 3 had higher early mortality: 23.7% of TNFd3/d3 homozygotes died before day 30, compared with 6.80% of non-d3/d3 recipients (P = .013). Recipients possessing longer IL-10-1064 microsatellite alleles developed more severe acute GVHD: 22.3% of recipients possessing alleles 12 to 15 developed grade III to IV GVHD, versus 3.92% of those with smaller alleles (P < .01). Other recipient or donor genotypes tested did not significantly affect GVHD or mortality. We conclude that recipient TNFd and IL-10-1064 polymorphisms associate with early mortality and severe acute GVHD in matched sibling BMT with dual prophyaxis. This supports the hypothesis of genetic predisposition towards GVHD and other BMT complications other than histocompatibility antigen disparity.

The effects of mismatching for DR antigens on renal allograft survival rates have largely been restricted to analyses of cadaver transplant results. Analyses of HLA matching in recipients of transplants from related donors have focused on the number of haplotypes shared between the recipients without regard to DR, or on the total number of HLA antigens mismatched, or on the degree of MLC responsiveness of the recipient to the donor. Most related donorrecipient pairs sharing only one HLA haplotype will be mismatched for DR at the other haplotype, but because there are a limited number of DR alleles, sharing of DR antigens on the mismatched haplotypes occurs relatively frequently. To determine the influence of mismatching for DR on the fate of renal allografts from related donors, we analyzed the results of 172 kidney transplants from related donors who shared one HLAABC haplotype with the recipient. There were 156 primary grafts and 16 retransplants 147 donorrecipient pairs were satisfactory typed for DR antigens. Because genotyping was not usually done, we performed two analyses under two different assumptions. The first assumption was that individuals expressing ≤1 DR antigen had null antigens, or were homozygous for DR the alternative assumption was that blanks were true antigens and individuals with blanks were heterozygous. The first assumption is more likely to be correct, and is the assumption used in most analyses of the effect of DR antigen mismatches on the results of cadaveric transplantation. Under the first assumption, of the 147 related donorrecipient pairs in whom DR typing was satisfactory, 33 were mismatched for 0, 64 for 1, and 3 for 2 DR antigens. The oneyear absolute graft survival rates in recipients of kidneys from donors with 0 mismatches for DR was 92 n49 in those with one mismatch for DR it was 82 n94 and from those with two mismatches it was 50 n4. The oneyear graft survival rate in 25 donorrecipient pairs in which one or both members could not be satisfactorily DR typed was 76. Differences in graft survival rates between the 0 and 1 and the 1 and 2 DRmismatched groups were not statistically significant. However, there was a difference in the number of recipients who required treatment for at least one rejection episode 24 of those who were 0 mismatched, 43 with 1 mismatch, 75 with two mismatches, and 44 of those not typed required antirejection treatment—and the difference between the 0 and the 1 mismatched groups was statistically significant P<.05. The demographic features of the four groups with regard to age, diabetes, splenectomy, transfusions, method of immunosuppression, and donor source were similar. Thus, we conclude that avoiding DR mismatches in recipients of renal allografts from livingrelated donors sharing one HLAABC haplotype may provide only a slight improvement in graft survival rates, but the need for antirejection treatment is significantly reduced.