Myeloid differentiation factor 88 signaling in donor T cells accelerates graft-versus-host disease.

Myeloid differentiation factor 88 (MyD88) signaling has a crucial role in activation of both innate and adoptive immunity. MyD88 transduces signals via Toll-like receptor and interleukin-1 receptor superfamily to the NFκB pathway and inflammasome by forming a molecular complex with interleukin-1 receptor-associated kinase 4. The MyD88/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 the pathophysiology of graft-versus-host disease (GvHD) remains to be elucidated. We addressed this issue by using MyD88-deficient T cells in a mouse model of allogeneic hematopoietic stem cell transplantation (allo-SCT). While MyD88-deficient and wild-type T cells proliferated equivalently after transplantation, MyD88-deficient T cells demonstrated impaired survival and differentiation toward Th1, Tc1, and Th17, and induced less severe GvHD compared to wild-type T cells. Administration of interleukin-1 receptor-associated kinase 4 inhibitor PF-06650833 significantly ameliorated GvHD after allo-SCT. These results thus demonstrate that donor T-cell MyD88/interleukin-1 receptor-associated kinase 4 pathway is a novel therapeutic target against GvHD after allo-SCT.

Graft-versus-host disease disrupts intestinal microbial ecology by inhibiting Paneth cell production of α-defensins.

Allogeneic hematopoietic stem cell transplantation (SCT) is a curative therapy for various hematologic disorders. Graft-versus-host disease (GVHD) and infections are the major complications of SCT, and their close relationship has been suggested. In this study, we evaluated a link between 2 complications in mouse models. The intestinal microbial communities are actively regulated by Paneth cells through their secretion of antimicrobial peptides, α-defensins. We discovered that Paneth cells are targeted by GVHD, resulting in marked reduction in the expression of α-defensins, which selectively kill noncommensals, while preserving commensals. Molecular profiling of intestinal microbial communities showed loss of physiologic diversity among the microflora and the overwhelming expansion of otherwise rare bacteria Escherichia coli, which caused septicemia. These changes occurred only in mice with GVHD, independently on conditioning-induced intestinal injury, and there was a significant correlation between alteration in the intestinal microbiota and GVHD severity. Oral administration of polymyxin B inhibited outgrowth of E coli and ameliorated GVHD. These results reveal the novel mechanism responsible for shift in the gut flora from commensals toward the widespread prevalence of pathogens and the previously unrecognized association between GVHD and infection after allogeneic SCT.

Diffuse panbronchiolitis after humanized anti-CCR4 monoclonal antibody therapy for relapsed adult T-cell leukemia/lymphoma.

We present the case of a 62-year-old Japanese woman with relapsed adult T-cell leukemia/lymphoma (ATLL) who was treated with humanized anti-CCR4 monoclonal antibody (KW-0761). Although this antibody was highly effective against refractory ATLL, 6 months after the final KW-0761 infusion, the patient complained of hypoxia due to diffuse panbronchiolitis. Physicians should remain vigilant to the possibility of such previously unreported late-onset adverse effects associated with KW-0761 therapy.

Pulmonary nocardiosis developed in a hematopoietic stem cell transplant recipient with bronchiolitis obliterans.

The chronic graft-versus-host disease often requires unceasing immunosuppressive therapy (IST), which increases a risk of infectious complications in hematopoietic stem cell transplantation (HSCT) recipients. We report an adult T-cell leukemia/lymphoma case who developed pulmonary nocardiosis, a rare pulmonary complication, after allogeneic HSCT despite administration of the prophylactic trimethoprim-sulfamethoxazole (TMP/STX). The inhaled corticosteroid in addition to systemic IST had been started for bronchiolitis obliterance 4 months prior to nocardiosis development. The patient was successfully treated with an increased dose of TMP/STX combined with meropenem. Transplantation physicians should keep this rare pulmonary complication in mind during sustained IST.