R-spondin1 stimulates the proliferation of intestinal stem cells through the Wnt signaling pathway and protects against graft-versus-host disease.

No abstract

Mogamulizumab (MOG), a humanized anti-CC chemokine receptor 4 (CCR4) monoclonal antibody, has recently played an important role in the treatment of adult T cell leukemia/lymphoma (ATLL). Because CCR4 is expressed on normal regulatory T cells as well as on ATLL cells, MOG may accelerate graft-versus-host disease (GVHD) by eradicating regulatory T cells in patients with allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, there is limited information about its safety and efficacy in patients treated with MOG before allo-HSCT. In the present study, 25 patients with ATLL were treated with MOG before allo-HSCT, after which 18 patients (72%) achieved remission. The overall survival and progression-free survival at 1 year post-transplantation were 20.2% (95% CI, 6.0% to 40.3%) and 15.0% (95% CI, 4.3% to 32.0%), respectively. The cumulative incidence of acute GVHD was 64.0% (95% CI, 40.7% to 80.1%) for grade II-IV and 34.7% (95% CI, 15.8% to 54.4%) for grade III-IV. The cumulative incidence of transplantation-related mortality (TRM) was 49.0% (95% CI, 27.0% to 67.8%). Six of 7 patients with acute GVHD grade III-IV died from GVHD, which was the leading cause of death. In particular, a shorter interval from the last administration of MOG to allo-HSCT was associated with more severe GVHD. MOG use before allo-HSCT may decrease the ATLL burden; however, it is associated with an increase in TRM due to severe GVHD. Because MOG is a potent anti-ATLL agent, new treatment protocols should be developed to integrate MOG at suitable doses and timing of administration to minimize unwanted GVHD development.

BackgroundIn East Asia, monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), previously known as type II enteropathy-associated T-cell lymphoma (EATL), occurs more frequently than type I EATL, and coeliac disease is rare.Case presentationHere we present four cases of MEITL in Japanese patients, including the endoscopic and pathological findings of their duodenal and colorectal lesions. Tumor specimens obtained from duodenal, intestinal, and colorectal biopsies in all four patients showed a diffuse intramucosal infiltration of small to/or medium-sized lymphoma cells and numerous atypical intraepithelial lymphocytes (IELs). These cells were immunohistologically positive for CD103, CD3, CD7, CD8, CD56, and T-cell intracellular antigen-1. Upper and lower gastrointestinal and antegrade double-balloon endoscopy revealed foci of edematous mucosa, with or without villous atrophy, in the non-neoplastic mucosa. Histological studies demonstrated duodenal and intestinal enteropathy-like lesions as well as microscopic (lymphocytic) proctocolitis with increased CD3- and CD8-positive and CD56-negative T-IELs in all four patients. The clinicopathological findings of the non-neoplastic lesions were similar to those characteristic of coeliac disease, suggesting that variants of coeliac disease may be present in the prodromal lesions of MEITL.ConclusionsOur study supports the need for random gastrointestinal biopsies to determine tumor spread, the features of MEITL in the particular patients, and the presence of prodromal non-neoplastic lesions.

We previously showed that transplantation with IL-21R gene-deficient splenocytes resulted in less severe graft-versus-host disease (GVHD) than was observed with wild type splenocytes. In this study, we sought to find mechanism(s) explaining this observation. Recipients of donor CD4+ T cells lacking IL-21R exhibited diminished GVHD symptoms, with reduced inflammatory cell infiltration into the liver and intestine, leading to prolonged survival. After transplantation, CD4+ T cell numbers in the spleen were reduced, and MLR and cytokine production by CD4+ T cells were impaired. These results suggest that IL-21 might promote GVHD through enhanced production of effector CD4+ T cells. Moreover, we found that CD25 depletion altered neither the impaired MLR in vitro nor the ameliorated GVHD symptoms in vivo. Thus, the attenuated GVHD might be caused by an impairment of effector T cell differentiation itself, rather than by an increase in regulatory T cells and suppression of effector T cells.

No abstract

Vaccination against vaccine-preventable diseases (VPDs) is highly recommended for hematopoietic stem cell transplantation (HSCT) recipients by several guidelines; however, the safety and seropositivity after live attenuated vaccines remain unclear in adult HSCT recipients. We analyzed titers of antibodies against measles, rubella, mumps, and varicella zoster virus (VZV) from Japanese adult patients who underwent allogeneic HSCT (allo-HSCT) (n = 74), autologous HSCT (auto-HSCT) (n = 39), or chemotherapy (n = 93). The seropositive rates for measles, rubella, mumps, and VZV in allo-HSCT recipients were 20.2%, 36.4%, 5.4%, and 55.4%, respectively. These rates were equivalent to those in auto-HSCT recipients but were significantly lower than those in patients receiving chemotherapy. Antibody titers tended to gradually decrease with time. Twenty-nine allo-HSCT recipients and 8 auto-HSCT recipients received live attenuated vaccines against VPDs for which they tested seronegative. The titers of antibodies against measles, rubella, and mumps significantly increased after 2 shots of vaccine, and the seropositive rate increased up to 19%, 30%, and 27%, respectively. Three patients (8.1%) experienced mild adverse events, which resolved promptly, indicating safe administration of the live attenuated vaccines. In multivariate analysis, history of chronic graft-versus-host disease was significantly associated with high seropositivity for measles as well as high seroconversion rate for measles after vaccination. Live attenuated vaccines against VPDs were safely administered in seronegative adult HSCT recipients. A further observational study is crucial to evaluate the efficacy of vaccination in seronegative HSCT patients.

The myeloid differentiation factor 88 signaling has a crucial role in activation of both innate and adoptive immunity. Myeloid differentiation factor 88 transduces signal via Toll-like receptor and interleukin-1 receptor superfamily to NFκB pathway and inflammasome by forming a molecular complex with interleukin-1 receptor-associated kinase 4. Myeloid differentiation factor 88/interleukin-1 receptor-associated kinase 4 pathway plays an important role not only in innate immunity but also T-cell immunity; however, its role in donor T cells on graft-versus-host disease pathophysiology remains to be elucidated. We addressed this issue by using myeloid differentiation factor 88-deficient T cells in a mouse model of allogeneic hematopoietic stem cell transplantation.While myeloid differentiation factor 88-deficient and wild-type T cells proliferated equivalently after transplantation, myeloid differentiation factor 88-deficient T cells demonstrated impaired survival and differentiation toward Th1, Tc1, and Th17, and induced less severe graft-versus-host disease compared to wild-type T cells. Administration of interleukin-1 receptor-associated kinase 4 inhibitor PF-06650833 significantly ameliorated graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. These results thus demonstrate that donor T-cell myeloid differentiation factor 88/ interleukin-1 receptor-associated kinase 4 pathway is a novel therapeutic target against graftversus-host disease after allogeneic hematopoietic stem cell transplantation.