Graft-versus-host disease (GVHD) remains a significant complication of allogeneic bone marrow transplantation (allo-BMT). Acute GVHD is mediated by immunocompetent donor T cells, which migrate to lymphoid tissues soon after infusion, recognize host alloantigens, and become activated upon interaction with host antigen-presenting cells (APCs). Recent work from our group and others suggests that activated effector T cells exit lymphoid tissues and traffic to mucosal sites and parenchymal target organs such as the gastrointestinal (GI) tract, liver, lung, and skin where they cause tissue damage. The molecular interactions necessary for effector cell migration during GVHD have become the focus of a growing body of research, as these interactions represent potential therapeutic targets. In this review we discuss chemokine and chemokine receptor interactions and adhesion molecules that have been shown to play roles in effector cell migration in experimental GVHD models, and we discuss a potential model for the role of chemokines during the activation phase of GVHD. (Blood. 2005;105: 4191-4199)

Graft-versus-host disease (GVHD) represents a major hurdle impeding the efficacy of allogeneic bone marrow transplantation (BMT). Bortezomib is a proteasome inhibitor that was recently approved for treatment of myeloma. We found that bortezomib potently inhibited in vitro mixed lymphocyte responses and promoted the apoptosis of alloreactive T cells. Bortezomib given at the time of allogeneic BMT in mice resulted in significant protection from acute GVHD. Reductions in GVHD-associated parameters and biological evidence of proteasome inhibition were observed with this regimen but with no adverse effects on long-term donor reconstitution. Assessment of graft-versus-tumor responses in advanced leukemia-bearing mice demonstrated that only the combination of allogeneic BMT and T cells with bortezomib promoted significant increases in survival. Increased cytotoxic T cell killing of the tumor was also observed. Thus, the combination of proteasome inhibition with selective immune attack can markedly increase the efficacy of BMT in cancer

CD4 ؉ CD25 ؉ regulatory T cells (T regs ) have been shown to inhibit graft-versus-host disease (GVHD) in murine models, and this suppression was mediated by T regs expressing the lymphoid homing molecule L-selectin. Here, we demonstrate that T regs lacking expression of the chemokine receptor CCR5 were far less effective in preventing lethality from GVHD. Survival of irradiated recipient animals given transplants supplemented with CCR5 ؊/؊ T regs was significantly decreased, and GVHD scores were enhanced compared with animals receiving wild-type (WT) T regs . CCR5 ؊/؊ T regs were functional in suppressing T-cell proliferation in vitro and ex vivo. However, although the accumulation of T regs within lymphoid tissues during the first week after transplantation was not dependent on CCR5, the lack of function of CCR5 ؊/؊ T regs correlated with impaired accumulation of these cells in the liver, lung, spleen, and mesenteric lymph node, more than one week after transplantation. These data are the first to definitively demonstrate a requirement for CCR5 in T reg function, and indicate that in addition to their previously defined role in inhibiting effector T-cell expansion in lymphoid tissues during GVHD, later recruitment of T regs to both lymphoid tissues and GVHD target organs is important in their ability to prolong survival after allogeneic bone marrow transplantation. ( IntroductionAcute graft-versus-host disease (GVHD) is a severe and potentially fatal complication of allogeneic bone marrow transplantation (allo-BMT). Acute GVHD is caused by mature donor T cells that recognize alloantigens presented initially by host antigen presenting cells (APCs). 1,2 Our group has demonstrated that the accumulation of donor T cells during the peritransplantation period takes place primarily in lymphoid tissues, followed by recruitment to parenchymal tissues such as the gastrointestinal (GI) tract, liver, lung, and skin. 3 We and others have recently demonstrated that eliminating expression of the chemokine receptor CCR5 from donor T cells in an experimental GVHD model resulted in exacerbated GVHD and increased T-cell infiltration of the liver and lung in lethally irradiated recipient animals. 4,5 These data suggested that the primary role for CCR5 during GVHD in conditioned transplant recipients is not to direct effector-cell recruitment as originally hypothesized, but to down-modulate target organ inflammation.Chemokines are predominantly 8-kDa to 12-kDa chemotactic proteins, which bind a family of 7-transmembrane-spanning G protein-coupled receptors, and function primarily in leukocyte migration (reviewed in Moser et al 6 ). The chemokine receptor CCR5 is expressed on activated T helper-1/T cytotoxic-1 (T H 1/ T C 1) T cells, natural killer (NK) cells, macrophages, and dendritic cells. 7 The ligands for this receptor, CCL3, CCL4, and CCL5, are expressed at sites of inflammation during acute GVHD. 4,[8][9][10][11] CCR5 may play a role in directing effector cells to sites of inflammation. [12][13][14][15] Interestingly howeve...

The coordinated expression of chemokines and receptors may be important in the directed migration of alloreactive T cells during graft-vs-host disease (GVHD). Recent work demonstrated in a murine model that transfer of CCR5-deficient (CCR5−/−) donor cells to nonconditioned haploidentical recipients resulted in reduced donor cell infiltration in liver and lymphoid tissues compared with transfer of CCR5+/+ cells. To investigate the function of CCR5 during GVHD in conditioned transplant recipients, we transferred CCR5−/− or wild-type C57BL/6 (B6) T cells to lethally irradiated B6D2 recipients. Unexpectedly, we found an earlier time to onset and a worsening of GVHD using CCR5−/− T cells, which was associated with significant increases in the accumulation of alloreactive CD4+ and CD8+ T cells in liver and lung. Conversely, the transfer of CCR5−/− donor cells to nonirradiated recipients led to reduced infiltration of target organs, confirming previous studies and demonstrating that the role of CCR5 on donor T cells is dependent on conditioning of recipients. Expression of proinflammatory chemokines in target tissues was dependent on conditioning of recipients, such that CXCL10 and CXCL11 were most highly expressed in tissues of irradiated recipients during the first week post-transplant. CCR5−/− T cells were shown to have enhanced migration to CXCL10, and blocking this ligand in vivo improved survival in irradiated recipients receiving CCR5−/− T cells. Our data indicate that the effects of inhibiting CCR5/ligand interaction on donor T cells during GVHD differ depending on conditioning of recipients, a finding with potentially important clinical significance.

NF-κB signaling through its -dependent canonical and-dependent noncanonical pathways plays distinctive roles in a diverse range of immune processes. Recently, mutations in these 2 genes have been associated with common variable immunodeficiency (CVID). While studying patients with genetically uncharacterized primary immunodeficiencies, we detected 2 novel nonsense gain-of-function (GOF) mutations (E418X and R635X) in 3 patients from 2 families, and a novel missense change (S866R) in another patient. Their immunophenotype was assessed by flow cytometry and protein expression; activation of canonical and noncanonical pathways was examined in peripheral blood mononuclear cells and transfected HEK293T cells through immunoblotting, immunohistochemistry, luciferase activity, real-time polymerase chain reaction, and multiplex assays. The S866R change disrupted a C-terminal NF-κΒ2 critical site affecting protein phosphorylation and nuclear translocation, resulting in CVID with adrenocorticotropic hormone deficiency, growth hormone deficiency, and mild ectodermal dysplasia as previously described. In contrast, the nonsense mutations E418X and R635X observed in 3 patients led to constitutive nuclear localization and activation of both canonical and noncanonical NF-κΒ pathways, resulting in a combined immunodeficiency (CID) without endocrine or ectodermal manifestations. These changes were also found in 2 asymptomatic relatives. Thus, these novel GOF mutations produce a nonfully penetrant CID phenotype through a different pathophysiologic mechanism than previously described for mutations in .

Background X-linked hyper-IgM syndrome (XHIGM) is a primary immunodeficiency with high morbidity and mortality compared with those seen in healthy subjects. Hematopoietic cell transplantation (HCT) has been considered a curative therapy, but the procedure has inherent complications and might not be available for all patients. Objectives We sought to collect data on the clinical presentation, treatment, and follow-up of a large sample of patients with XHIGM to (1) compare long-term overall survival and general well-being of patients treated with or without HCT along with clinical factors associated with mortality and (2) summarize clinical practice and risk factors in the subgroup of patients treated with HCT. Methods Physicians caring for patients with primary immunodeficiency diseases were identified through the Jeffrey Modell Foundation, United States Immunodeficiency Network, Latin American Society for Immunodeficiency, and Primary Immune Deficiency Treatment Consortium. Data were collected with a Research Electronic Data Capture Web application. Survival from time of diagnosis or transplantation was estimated by using the Kaplan-Meier method compared with log-rank tests and modeled by using proportional hazards regression. Results Twenty-eight clinical sites provided data on 189 patients given a diagnosis of XHIGM between 1964 and 2013; 176 had valid follow-up and vital status information. Sixty-seven (38%) patients received HCT. The average follow-up time was 8.5 ± 7.2 years (range, 0.1–36.2 years). No difference in overall survival was observed between patients treated with or without HCT (P = .671). However, risk associated with HCT decreased for diagnosis years 1987–1995; the hazard ratio was significantly less than 1 for diagnosis years 1995–1999. Liver disease was a significant predictor of overall survival (hazard ratio, 4.9; 95% confidence limits, 2.2–10.8; P < .001). Among survivors, those treated with HCT had higher median Karnofsky/Lansky scores than those treated without HCT (P < .001). Among patients receiving HCT, 27 (40%) had graft-versus-host disease, and most deaths occurred within 1 year of transplantation. Conclusion No difference in survival was observed between patients treated with or without HCT across all diagnosis years (1964–2013). However, survivors treated with HCT experienced somewhat greater well-being, and hazards associated with HCT decreased, reaching levels of significantly less risk in the late 1990s. Among patients treated with HCT, treatment at an early age is associated with improved survival. Optimism remains guarded as additional evidence accumulates.

Conflict of interest: MLM developed thymus transplantation intellectual property, which has been licensed to Enzyvant Therapeutics. Both MLM and Duke University may benefit financially if the technology is commercially successful in the future.

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