Allogeneic (allo) hematopoietic stem cell transplantation is an effective therapy for hematological malignancies but it is limited by acute graft-versus-host disease (GVHD). Dendritic cells (DC) play a major role in the allo T cell stimulation causing GVHD. Current immunosuppressive measures to control GVHD target T cells but compromise posttransplant immunity in the patient, particularly to cytomegalovirus (CMV) and residual malignant cells. We showed that treatment of allo mixed lymphocyte cultures with activated human DC-depleting CD83 antibody suppressed alloproliferation but preserved T cell numbers, including those specific for CMV. We also tested CD83 antibody in the human T cell–dependent peripheral blood mononuclear cell transplanted SCID (hu-SCID) mouse model of GVHD. We showed that this model requires human DC and that CD83 antibody treatment prevented GVHD but, unlike conventional immunosuppressants, did not prevent engraftment of human T cells, including cytotoxic T lymphocytes (CTL) responsive to viruses and malignant cells. Immunization of CD83 antibody-treated hu-SCID mice with irradiated human leukemic cell lines induced allo antileukemic CTL effectors in vivo that lysed 51Cr-labeled leukemic target cells in vitro without further stimulation. Antibodies that target activated DC are a promising new therapeutic approach to the control of GVHD.

Summary:We investigated the role of polymorphism of the vitamin D receptor (VDR) gene in HLA-matched sibling BMT for polymorphisms previously associated with human disease pathology. In intron 8 of the VDR gene, the B and A alleles of the BsmI and ApaI RFLPs were found to associate with reduced aGVHD when present in the patient's genotype. Logistic regression analysis demonstrated that patient VDR genotype, along with previously identified IL-10 ؊1064 and IFN-␥ genotype to be risk factors for severe acute GVHD. The A allele also associates with increased likelihood of death when present in the donor genotype (AA vs Aa or aa, hazard ratio 2.03, P = 0.0232). In patients who received increased prophylaxis with multi-agent therapy, patients whose graft was from a donor with an AA genotype had a substantially worse survival than patients whose graft was from a donor with a non-AA genotype (hazard ratio 12. and poly-A polymorphisms are in linkage disequilibrium with each other. It is proposed that these polymorphisms exert their effects through enhanced transcription of the VDR gene or through altered mRNA stability. 5,6 The role of vitamin D3 and of the VDR in bone metabolism and turnover is well established. Homozygosity for the closely linked bb and aa genotypes of the BsmI and ApaI RFLPs in intron 8 is associated with increased femoral and vertebral bone density. 3,4,7 Reduced bone loss associated with liver transplantation is less frequent in transplant patients who possess the BsmI and ApaI aa and bb genotypes for VDR. 8 Polymorphism at the ATG initiation codon (FokI site) has been associated with genetic determination of final height in Japanese subjects, with heterozygotes at this locus achieving a greater final height than homozygotes for either allele, 1 and with heritable variation in bone mineral density. 9 Polymorphism at both the FokI and TaqI sites has been associated with variation in intervertebral disc degeneration in males. 10

Interleukin 1 (IL‐1) is involved in various autoimmune and inflammatory diseases. IL‐1 receptor antagonist (IL‐1Ra) is the naturally occurring antagonist to IL‐1α and ‐1β. Polymorphisms of IL‐1β have been associated with variations in IL‐1β production (nucleotides +3953 and −511). A variable number tandem repeat (VNTR) polymorphism in the IL‐1Ra gene has been associated (allele 2) with increased IL‐1Ra production. We examined these polymorphisms in human leucocyte antigen (HLA)‐matched allogeneic bone marrow transplant patients and donors. IL‐1Ra VNTR (allele 2) in the donor genotype was more frequent with milder acute graft‐versus‐host disease (aGvHD) grades 0–II (29 out of 59 transplants) than severe GvHD grades III–IV (2 out of 18 transplants) (P = 0·0032). This association was confirmed in a subgroup with cyclosporine monotherapy prophylaxis: donor possession of allele 2 was again associated with milder aGvHD, grades 0–II (19 out of 38 transplants), than grades III–IV (1 out of 14) (P = 0·0042) transplants. No association was found between the IL‐1β−511 or IL‐1β+3953 polymorphism and severity of GvHD. Recipient IL‐1Ra VNTR genotype (allele 2) showed a strong trend towards association with aGvHD severity (P = 0·0697). Thus, the donor genotype for the IL‐1Ra polymorphism has an apparent protective role against acute GvHD following transplantation and may be an additional factor for individual risk assessment for complications, including GvHD, post transplant.

After allogeneic stem cell transplantation, the establishment of the donor's immune system in an antigenically distinct recipient confers a therapeutic graft-versus-malignancy effect, but also causes graft-versus-host disease (GVHD) and protracted immune dysfunction. In the last decade, a molecular-level description of alloimmune interactions and the process of immune recovery leading to tolerance has emerged. Here, new developments in understanding alloresponses, genetic factors that modify them, and strategies to control immune reconstitution are described.In Section I, Dr. John Barrett and colleagues describe the cellular and molecular basis of the alloresponse and the mechanisms underlying the three major outcomes of engraftment, GVHD and the graft-versus-leukemia (GVL) effect. Increasing knowledge of leukemia-restricted antigens suggests ways to separate GVHD and GVL. T cellsThe alloresponse segregates into induction, expansion, and effector phases. In the induction phase, donor CD8 and CD4 T cells interact with peptide antigens complexed with major histocompatibility complex (MHC) class I and II molecules, respectively, on antigen-presenting cells (APCs) of the recipient. The signal given by the MHC through the T-cell receptor (TCR) and CD3, CD4, or CD8 provides the first signal for Tcell activation. A full T-cell response, leading to proliferation of effector cells, requires a second signal delivered by interaction by costimulatory molecules such as CD80 and CD86 on the APCs and CD28 on the lymphocyte surface. During the expansion phase, T cells proliferate, particularly under the influence of growth factors interleukin (IL)-2 and IL-12. The milieu in which T cells expand determines whether they assume the characteristics of T helper (Th) or T cytotoxic (Tc) type 1, or Th/Tc type 2 cells, which have distinct proor antiinflammatory functional properties, respectively.