Adoptive transfer of T cells reactive to minor histocompatibility antigens has the unmatched ability to eradicate malignant hematopoietic cells. Unfortunately, its use is hampered by the associated graft-versus-host disease. The critical issue of a possible dissociation of the antileukemic effect and graft-versus-host disease by targeting specific minor histocompatibility antigens remains unresolved because of the unknown nature and number of minor histocompatibility antigens necessary or sufficient to elicit anti-leukemic activity and graft-versus-host disease. We found that injection of T lymphocytes primed against a single major histocompatibility complex class I-restricted immunodominant minor histocompatibility antigen (B6dom1) caused no graft-versus-host disease but produced a curative anti-leukemic response. Avoidance of graft-versus-host disease required that no other host-reactive T cells be co-injected with T cells primed with B6dom1. Here we show that effective and non-toxic immunotherapy of hematologic malignancies can be achieved by targeting a single immunodominant minor histocompatibility antigen.

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1 The potent coronary vasoconstrictor, endothelin-1 (ET-1) may also regulate neutrophil tra c into tissues. The aim of the present study was to characterize the endothelin receptors responsible and to investigate the underlying mechanisms. 2 ET-1 (1 nM ± 1 mM) markedly enhanced attachment of human neutrophils to lipopolysaccharide-, and to a lesser extent, to ET-1-activated human coronary artery endothelial cells (HCAEC). This can partially be blocked by monoclonal antibodies against E-selectin, L-selectin or CD18, whereas combination of the three antibodies inhibited adhesion by *83%. Increases in neutrophil adhesion evoked by ET-1 were also blocked by the platelet-activating factor (PAF) antagonists, BN 52021 (50 mM) and WEB 2086 (10 mM). 3 ET-1 downregulated the expression of L-selectin and upregulated expression of CD11b/CD18 and CD45 on the neutrophil surface and induced gelatinase release with EC 50 values of *2 nM. These actions of ET-1 were almost completely prevented by the ET A receptor antagonist FR 139317 (1 mM) and the ET A /ET B receptor antagonist bosentan (10 mM), whereas the ET B receptor antagonist BQ 788 (1 mM) had no e ect. ET-1 slightly increased the expression of E-selectin and ICAM-1 on HCAEC, that was prevented by BQ 788, but not by FR 139317.

BackgroundGraft-versus-host disease (GVHD) results from recognition of host antigens by donor T cells following allogeneic hematopoietic cell transplantation (AHCT). Notably, histoincompatibility between donor and recipient is necessary but not sufficient to elicit GVHD. Therefore, we tested the hypothesis that some donors may be “stronger alloresponders” than others, and consequently more likely to elicit GVHD.Methods and FindingsTo this end, we measured the gene-expression profiles of CD4+ and CD8+ T cells from 50 AHCT donors with microarrays. We report that pre-AHCT gene-expression profiling segregates donors whose recipient suffered from GVHD or not. Using quantitative PCR, established statistical tests, and analysis of multiple independent training-test datasets, we found that for chronic GVHD the “dangerous donor” trait (occurrence of GVHD in the recipient) is under polygenic control and is shaped by the activity of genes that regulate transforming growth factor-β signaling and cell proliferation.ConclusionsThese findings strongly suggest that the donor gene-expression profile has a dominant influence on the occurrence of GVHD in the recipient. The ability to discriminate strong and weak alloresponders using gene-expression profiling could pave the way to personalized transplantation medicine.