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Posttransplantation cyclophosphamide (PTCy) has become a popular option for haploidentical hematopoietic stem cell transplantation (HSCT). However, personalized methods to adjust immune intensity after PTCy for each patient's condition have not been well studied. Here, we investigated the effects of reducing the dose of PTCy followed by α-galactosylceramide (α-GC), a ligand of iNKT cells, on the reciprocal balance between graft-versus-host disease (GVHD) and the graft-versus-leukemia (GVL) effect. In a murine haploidentical HSCT model, insufficient GVHD prevention after reduced-dose PTCy was efficiently compensated for by multiple administrations of α-GC. The ligand treatment maintained the enhanced GVL effect after reduced-dose PTCy. Phenotypic analyses revealed that donor-derived B cells presented the ligand and induced preferential skewing to the NKT2 phenotype rather than the NKT1 phenotype, which was followed by the early recovery of all T cell subsets, especially CD4+Foxp3+ regulatory T cells. These studies indicate that α-GC administration soon after reduced-dose PTCy restores GVHD-preventing activity and maintains the GVL effect, which is enhanced by reducing the dose of PTCy. Our results provide important information for the development of a novel strategy to optimize PTCy-based transplantation, particularly in patients with a potential relapse risk. [ABSTRACT FROM AUTHOR]

Abstract: A 52‐year‐old man suffered from progressive multifocal leukoencephalopathy (PML) after human leukocyte antigen (HLA)‐haploidentical transplantation with post‐transplantation cyclophosphamide (PTCY). Mirtazapine, mefloquine, and cytarabine failed to improve his symptoms, and he finally died 4.5 months after PML onset. This is the first case report of a patient with PML after HLA‐haploidentical transplantation with PTCY. Although T‐cell replete HLA‐haploidentical transplantation with PTCY has enabled early immune reconstitution, PML should be considered if a patient's mental condition deteriorates. [ABSTRACT FROM AUTHOR]

Mogamulizumab (Mog), a humanized anti-CCR4 antibody, provides an important treatment option for relapsed/refractory adult T cell leukemia/lymphoma. However, administration of Mog before allogenic hematopoietic stem cell transplantation has been reported to be a risk factor for severe acute graft-versus-host disease (GVHD). The etiological hypothesis is Mogamulizumab may eradicate CCR4-positive regulatory T cells (Tregs). Theoretically, Treg homeostasis and course of GVHD can be affected by plasma exchange (PE) with decreasing plasma Mog concentration. Here, we present a case of severe acute GVHD after pretransplantation Mog, in which PE was performed for liver failure. As a result, plasma Mog concentration was decreased but it did not lead to the prompt elevation of Treg levels in peripheral blood and clinical responses of GVHD were limited to partial remission. Our case suggests that recovery of donor-derived Treg in the acute phase after HSCT is multifactorial and the single procedure of PE-based Mog depletion does not necessarily warrant the quick restoration of Treg homeostasis. [ABSTRACT FROM AUTHOR]

Graft-versus-host disease (GVHD) triggered by activated donor graft cells still remains a major complication and course of non-relapse mortality after HSCT. Interleukin-2-inducible T-cell kinase (ITK) is a TEC family cytoplasmic tyrosine kinase of crucial importance for T cell development and TCR signaling. Recent studies demonstrated that ITK-deficient CD4+ T cells easily differentiated into regulatory T cells (Tregs) and ITK/BTK inhibitor ibrutinib could improve chronic GVHD symptoms in mouse model and human clinical study, suggesting that ITK may have important roles in post-transplant immune tolerance. In this study, we examined the effects of ITK-selective inhibitor (ITKsi; ONO-7790500) on acute GVHD by using murine BMT model. Allogeneic response of ITKsi-treated CD4+ T cells from B6 was evaluated by in vitro system and murine BMT model. In BMT experiments, lethally irradiated 10-week old B6D2F1 recipient mice were transplanted with 5 × 106 TCD BM together with 1.5 × 106 CD4+ T cells from B6 donors. Survival and GVHD severity were clinically monitored, and T cell subset reconstitution and serum cytokine profile were also examined. First, to examine the influence of ITKsi on alloreactive T cell to the corresponding antigens in vitro, CD4+ T cells isolated from B6 mice were exposed to ITKsi for 3 hours and then cultured with irradiated Balb/c stimulators. Proliferation and IFN-gamma production of ITKsi-treated T cells in response to allogeneic stimulators were significantly reduced in comparison to those from controls (P < 0.0001, < 0.0001, respectively). As expected, ITKsi-treatment did not interfere with Treg maintenance. Analysis of transcription factors revealed that the expressions of both T-bet and GATA3 were suppressed in ITKsi-treated T cells. We then performed experimental allogeneic BMT. In ITKsi-treated group, donor CD4+ T cells were cultured in the presence of ITKsi during 3 hours just before transplant. GVHD mortality was significantly less in recipients of ITKsi-treated donor graft than in those of a control graft (10% vs 64.5% on day 60, p < 0.01). Early proliferation of donor T cells and the production of proinflammatory cytokines including TNF-alpha and IL-2 in the first week after transplant were significantly reduced in ITKsi-treated group than control group (P = 0.04, 0.003, respectively). Th2 cytokines, IL-4 and IL-5, were also suppressed. Taken together, these data showed that pretreatment of CD4+ T cells with ITKsi efficiently regulated alloreactive T cell and improved the symptoms of acute GVHD. ITKsi inhibited both Th1 and Th2 response but spared the expansion of donor-derived Tregs. Our findings suggest that graft manipulation with short-term culture with ITKsi just before transplant could provide a simple but efficient strategy to modulate alloreactive T cell response and clinical GVHD. [ABSTRACT FROM AUTHOR]