[Current state of graft-versus-host disease prophylaxis with PTCy for allogeneic hematopoietic stem cell transplantation].

There is growing recognition of post-transplant cyclophosphamide (PTCy) as the new standard prophylaxis for graft-versus-host disease (GVHD) in HLA-matched peripheral blood stem cell transplants with reduced intensity conditioning, based on recent results of randomized phase III trials of PTCy. Allogeneic hematopoietic cell transplantation (HCT) with PTCy is thought to have GVHD-dependent and -independent graft-versus-tumor (GVT) effects. Its GVHD-dependent effects may be attenuated by PTCy-induced alloreactive T cell dysfunction and preferential recovery of regulatory T cells after HCT, but its GVT effects do not appear to be significantly impaired in patients in remission or with indolent disease. As patients not in remission are often also candidates for transplantation in Japan, it will be necessary to use PTCy as a platform to establish a strategy that could also be effective in patients not in remission and to revise the donor selection algorithm.

Graft-versus-tumor effect of post-transplant cyclophosphamide-based allogeneic hematopoietic cell transplantation.

Post-transplant cyclophosphamide (PTCy) is becoming the standard prophylaxis for graft-versus-host disease (GVHD) in HLA-haploidentical allogeneic hematopoietic cell transplantation (allo-HCT) and in HLA-matched allo-HCT. Immune reconstitution in the post-transplant setting may influence the graft-versus-tumor (GVT) effect because PTCy has a profound effect on T cell and natural killer cell functions and their reconstitution after allo-HCT. However, many recent studies have shown that the incidence of relapse after allo-HCT with PTCy is comparable to that after conventional allo-HCT. To further improve the outcomes, it is critical to establish a strategy to maintain or effectively induce the GVT effect when using PTCy as a platform for GVHD prophylaxis. However, there is a paucity of studies focusing on the GVT effect in allo-HCT with PTCy. Therefore, focusing on this issue may lead to the establishment of more appropriate strategies to improve transplantation outcomes without exacerbating GVHD, including novel therapies involving cell modification.

Granulocyte-Macrophage Colony-Stimulating Factor in Allogenic Hematopoietic Stem Cell Transplantation: From Graft-versus-Host Disease to the Graft-versus-Tumor Effect.

Allogenic hematopoietic stem cell transplantation (allo-HSCT) is a widely used treatment for a broad range of hematologic malignancies because of its graft-versus-tumor (GVT) effect. Unfortunately, allo-HSCT is still associated with morbidity and mortality related to relapse and transplantation complications, namely graft-versus-host-disease (GVHD). In an era of therapies specifically targeting molecular pathways, transcription factors, and cytokines, a better understanding of GVHD physiopathology is essential for the development of new therapeutic approaches. In this review, we outline the current knowledge of the role of granulocyte- macrophage colony-stimulating factor (GM-CSF) in allo-HSCT. We first discuss the biology of GM-CSF and its signaling pathways, with a focus on the main producing cells, T cells. We discuss recent preclinical studies pointing to a pivotal role of GM-CSF in GVHD, in particular gastrointestinal GVHD. We then summarize the potential role of GM-CSF in the GVT effect, discussing some potential strategies for exploiting GM-CSF in the context of allo-HSCT.

Regulatory T Cell Amelioration of Graft-versus-Host Disease following Allogeneic/Xenogeneic Hematopoietic Stem Cell Transplantation Using Mobilized Mouse and Human Peripheral Blood Donors.

The present studies examined experimental transplant outcomes using mobilized peripheral blood from mice and humans together with FoxP3+Treg cells. Donor mice were treated with filgrastim and / or plerixafor and their peripheral blood (PB) displayed significant elevations in hematopoietic stem and progenitor populations. Some of these PB donors were concurrently administered a Treg expansion strategy consisting of a TL1A-Ig fusion protein low dose rIL-2. A significant increase (4-5x) in the frequency Tregs occurred during mobilization. C3H.SW PB was collected from mobilized and Treg unexpanded ("TrUM") or mobilized and Treg expanded ("TrEM") donors and transplanted into MHC-matched B6 (H2b) recipients. Recipients of TrEM, exhibited significantly reduced weight loss and clinical GVHD scores compared to recipients of TrUM. Notably, recipients of TrEM exhibited comparable GVL activity to TrUM recipients against leukemia levels. Next, huTregs (CD4+CD25+CD127lo) from a healthy human PB mobilized donor were expanded ex-vivo prior to transplant into NSG/ NOD-scid IL2Rgammanull mice. We found that treatment with ex-vivo expanded huTregs resulted in significant reduction of lethality and clinical xGVHD scores. Notably, post-transplant, PB huTregs levels remained elevated and the frequency of huCD4+Tconv and CD8+ cells was diminished supporting the improved xGVHD outcomes. These findings demonstrated that the use of mPB containing elevated Treg levels significantly reduced GVHD following "MUD" and MHC-mismatched mouse HSCT without loss of GVL activity. Moreover, utilizing ex-vivo expanded huTregs from a mobilized PB donor and added back to donor PB ameliorated xGVHD. In total, these studies support the notion that in vivo or ex-vivo manipulation of donor Tregs together with mobilized peripheral blood could provide therapeutic approaches to improve aHSCT outcomes.

Graft-Versus-Host Disease Prevention by In Vitro-Generated Myeloid-Derived Suppressor Cells Is Exclusively Mediated by the CD11b+CD11c+ MDSC Subpopulation.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of myeloid progenitor cells that dampen overwhelming adaptive immune responses through multiple mechanisms and are recognized as an attractive novel immune intervention therapy for counteracting the destructive effects of graft- versus -host disease (GVHD) developing after allogeneic bone marrow transplantation (BMT). MDSCs can be produced in great numbers for cellular therapy, but they present a mixture of subsets whose functions in GVHD prevention are undefined. Here, we generated MDSCs in vitro from murine BM cells in the presence of GM-CSF and defined the integrin CD11c as a marker to subdivide MDSCs into two functional subgroups: CD11b+CD11c+ and CD11b+CD11c- MDSCs. Isolated CD11b+CD11c+ and CD11b+CD11c- MDSCs both inhibited alloantigen-stimulated T-cell proliferation in vitro, although CD11b+CD11c+ MDSCs were more efficient and expressed higher levels of different immunosuppressive molecules. Likewise, expression of surface markers such as MHC class II, CD80, CD86, or PD-L1 further delineated both subsets. Most importantly, only the adoptive transfer of CD11b+CD11c+ MDSCs into a single MHC class I-disparate allogeneic BMT model prevented GVHD development and strongly decreased disease-induced mortality, while CD11b+CD11c- MDSCs were totally ineffective. Surprisingly, allogeneic T-cell homing and expansion in lymphatic and GVHD target organs were not affected by cotransplanted CD11b+CD11c+ MDSCs indicating a clear contradiction between in vitro and in vivo functions of MDSCs. However, CD11b+CD11c+ MDSCs shifted immune responses towards type 2 immunity reflected by increased Th2-specific cytokine expression of allogeneic T cells. Induction of type 2 immunity was mandatory for GVHD prevention, since CD11b+CD11c+ MDSCs were ineffective if recipients were reconstituted with STAT6-deficient T cells unable to differentiate into Th2 cells. Most importantly, the beneficial graft- versus -tumor (GVT) effect was maintained in the presence of CD11b+CD11c+ MDSCs since syngeneic tumor cells were efficiently eradicated. Strong differences in the transcriptomic landscape of both subpopulations underlined their functional differences. Defining CD11b+CD11c+ MDSCs as the subset of in vitro-generated MDSCs able to inhibit GVHD development might help to increase efficiency of MDSC therapy and to further delineate relevant target molecules and signaling pathways responsible for GVHD prevention.

T-Cell Metabolism in Graft Versus Host Disease.

Allogeneic-hematopoietic stem cell transplantation (allo-HSCT) represents the only curative treatment option for numerous hematological malignancies. Elimination of malignant cells depends on the T-cells' Graft-versus-Tumor (GvT) effect. However, Graft-versus-Host-Disease (GvHD), often co-occurring with GvT, remains an obstacle for therapeutic efficacy. Hence, approaches, which selectively alleviate GvHD without compromising GvT activity, are needed. As already explored for autoimmune and inflammatory disorders, immuno-metabolic interventions pose a promising option to address this unmet challenge. Being embedded in a complex regulatory framework, immunological and metabolic pathways are closely intertwined, which is demonstrated by metabolic reprograming of T-cells upon activation or differentiation. In this review, current knowledge on the immuno-metabolic signature of GvHD-driving T-cells is summarized and approaches to metabolically interfere are outlined. Furthermore, we address the metabolic impact of standard medications for GvHD treatment and prophylaxis, which, in conjunction with the immuno-metabolic profile of alloreactive T-cells, could allow more targeted interventions in the future.

Human Wnt/ß-Catenin Regulates Alloimmune Signaling during Allogeneic Transplantation.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is one of the most widely applied forms of adoptive immunotherapy for the treatment of hematological malignancies. Detrimental graft-versus-host disease (GVHD), but also beneficial graft-versus-leukemia (GVL) effects occurring after allo-HSCT are largely mediated by alloantigen-reactive donor T cells in the graft. Separating GVHD from GVL effects is a formidable challenge, and a greater understanding of donor T cell biology is required to accomplish the uncoupling of GVHD from GVL. Here, we evaluated the role of ß-catenin in this process. Using a unique mouse model of transgenic overexpression of human ß-catenin (Cat-Tg) in an allo-HSCT model, we show here that T cells from Cat-Tg mice did not cause GVHD, and surprisingly, Cat-Tg T cells maintained the GVL effect. Donor T cells from Cat-Tg mice exhibited significantly lower inflammatory cytokine production and reduced donor T cell proliferation, while upregulating cytotoxic mediators that resulted in enhanced cytotoxicity. RNA sequencing revealed changes in the expression of 1169 genes for CD4, and 1006 genes for CD8+ T cells involved in essential aspects of immune response and GVHD pathophysiology. Altogether, our data suggest that ß-catenin is a druggable target for developing therapeutic strategies to reduce GVHD while preserving the beneficial GVL effects following allo-HSCT treatment.

Reconstructing high-resolution gridded precipitation data using an improved downscaling approach over the high altitude mountain regions of Upper Indus Basin (UIB).

Understanding the basin-scale hydrology and the spatiotemporal distribution of regional precipitation requires high precision, as well as high-resolution precipitation data. We have made an attempt to develop an Integrated Downscaling and Calibration (IDAC) framework to generate high-resolution (1 km × 1 km) gridded precipitation data. Traditionally, GWR (Geographical weighted regression) model has widely been applied to generate high-resolution precipitation data for regional scales. The GWR model generally assumes a spatially varied relationships between precipitation and its associated environmental variables, however, the relationships need to remain constant (fixed) for some variables over space. In this study, a Mixed Geographically Weighted Regression (MGWR) model, capable of dealing with the fixed and spatially varied environmental variables, is proposed to downscale the Original-TRMM precipitation data from a coarse resolution (0.25o × 0.25o) to a high-resolution (1 km × 1 km) for the period of 2000-2018 over the Upper Indus Basin (UIB). Additionally, accuracy of the downscaled precipitation data was further improved by merging it with the recorded data from rain gauge stations (RGS) using two calibration approaches such as Geographical Ratio Analysis (GRA) and Geographical Difference Analysis (GDA). We found MGWR to perform better given its higher R2 and lower RMSE and bias values (R2 = 0.96; RMSE = 56.01 mm, bias = 0.014) in comparison to the GWR model (R2 = 0.95; RMSE = 60.76 mm, bias = 0.094). It was observed that the GDA and GRA calibrated-downscaled precipitation datasets were superior to the Original-TRMM, yet GRA outperformed GDA. Annual precipitation from downscaled and calibrated-downscaled datasets was further temporally downscaled to obtain high-resolution monthly and daily precipitations. The results revealed that the monthly-downscaled precipitation (R2 = 0.82, bias = -0.02 and RMSE = 11.93 mm/month) and the calibrated-downscaled (R2 = 0.89, bias = -0.006 and RMSE = 9.19 mm/month) series outperformed the Original-TRMM (R2 = 0.72, bias = 0.14 and RMSE = 19.8 mm/month) as compared to the RGS observations. The results of daily calibrated-downscaled precipitation (R2 = 0.79, bias = 0.001 and RMSE = 1.7 mm/day) were better than the Original-TRMM (R2 = 0.64, bias = - 0.12 and RMSE = 6.82 mm/day). In general, the proposed IDAC approach is suitable for retrieving high spatial resolution gridded data for annual, monthly, and daily time scales over the UIB with varying climate and complex topography.

Rapamycin-based graft-versus-host disease prophylaxis increases the immunosuppressivity of myeloid-derived suppressor cells without affecting T cells and anti-tumor cytotoxicity.

The immunosuppressant rapamycin (RAPA) inhibits mammalian target of rapamycin (mTOR) functions and is applied after allogeneic bone marrow transplantation (BMT) to attenuate the development of graft-versus-host disease (GVHD), although the cellular targets of RAPA treatment are not well defined. Allogeneic T cells are the main drivers of GVHD, while immunoregulatory myeloid-derived suppressor cells (MDSCs) were recently identified as potent disease inhibitors. In this study, we analyzed whether RAPA prevents the deleterious effects of allogeneic T cells or supports the immunosuppressive functions of MDSCs in a BMT model with major histocompatibility complex (MHC) classes I and II disparities. RAPA treatment efficiently attenuated clinical and histological GVHD and strongly decreased disease-induced mortality. Although splenocyte numbers increased during RAPA treatment, the ratio of effector T cells to MDSCs was unaltered. However, RAPA treatment induced massive changes in the genomic landscape of MDSCs preferentially up-regulating genes responsible for uptake or signal transduction of lipopeptides and lipoproteins. Most importantly, MDSCs from RAPA-treated mice exhibited increased immunosuppressive potential, which was primarily inducible nitric oxide synthase (iNOS)-dependent. Surprisingly, RAPA treatment had no impact on the genomic landscape of T cells, which was reflected by unchanged expression of activation and exhaustion markers and cytokine profiles in T cells from RAPA-treated and untreated mice. Similarly, T cell cytotoxicity and the graft-versus-tumor effect were maintained as co-transplanted tumor cells were efficiently eradicated, indicating that the immunosuppressant RAPA might be an attractive approach to strengthen the immunosuppressive function of MDSCs without affecting T cell immunity.

Myeloid-Derived Suppressor Cells in the Context of Allogeneic Hematopoietic Stem Cell Transplantation.

Myeloid-derived suppressor cells (MDSCs) are innate immune cells that acquire the capacity to suppress adaptive immune responses. In the context of allogeneic hematopoietic stem cell transplantation (allo-HSCT), MDSCs (in the donor graft and in the recipient, after allo-HSCT) might mediate immune suppression through multiple mechanisms. However, it remains unclear how MDSCs can be distinguished from their normal myeloid counterparts in the hematopoietic stem cell donor graft and during immune reconstitution after allo-HSCT in the recipient. Our ability to understand their exact role in allo-HSCT is limited by the absence of a specific gene signature or surface markers for identifying MDSCs among myeloid cells and by their plasticity in different microenvironments. According to various studies, MDSCs might induce transplant tolerance and control graft vs. host disease (GVHD), but their impact on the graft vs. tumor effect (GVT) is not fully understood. In fact, we know that MDSCs commonly expand in patients with cancer, and they are thought to promote hematological malignancy progression. However, little is known about whether depleting them might be an effective strategy for enhancing GVT effects. Here, we review data published over the past 40 years on allo-HSCT to delineate the different MDSC subsets, and their abilities to induce transplant tolerance and preserve the GVT effect. This review will provide a basis for determining whether one MDSC subset might be proposed as the most appropriate candidate for cellular therapies, due to its ability to modulate GVHD.

The IL-12 Cytokine and Receptor Family in Graft-vs.-Host Disease.

Allogeneic hematopoietic cell transplantation (allo-HCT) is performed with curative intent for high- risk blood cancers and bone marrow failure syndromes; yet the development of acute and chronic graft-vs.-host disease (GVHD) remain preeminent causes of death and morbidity. The IL-12 family of cytokines is comprised of IL-12, IL-23, IL-27, IL-35, and IL-39. This family of cytokines is biologically distinct in that they are composed of functional heterodimers, which bind to cognate heterodimeric receptor chains expressed on T cells. Of these, IL-12 and IL-23 share a common ß cytokine subunit, p40, as well as a receptor chain: IL-12Rß1. IL-12 and IL-23 have been documented as proinflammatory mediators of GVHD, responsible for T helper 1 (Th1) differentiation and T helper 17 (Th17) stabilization, respectively. The role of IL-27 is less defined, seemingly immune suppressive via IL-10 secretion by Type 1 regulatory (Tr1) cells yet promoting inflammation through impairing CD4+ T regulatory (Treg) development and/or enhancing Th1 differentiation. More recently, IL-35 was described as a potent anti-inflammatory agent produced by regulatory B and T cells. The role of the newest member, IL-39, has been implicated in proinflammatory B cell responses but has not been explored in the context of allo-HCT. This review is directed at discussing the current literature relevant to each IL-12-family cytokine and cognate receptor engagement, as well as the consequential downstream signaling implications, during GVHD pathogenesis. Additionally, we will provide an overview of translational strategies targeting the IL-12 family cytokines, their receptors, and subsequent signal transduction to control GVHD.

Can cytoplasmic donation rescue aged oocytes?

BACKGROUND: The pregnancy and delivery rates following assisted reproductive technology (ART) start to decrease and that the miscarriage rate increases rapidly from 35 years old. The miscarriage rate exceeds 50% at 43 years old. The number of aneuploid fetuses in miscarriages increases according to female age, reaching more than 90% when women are over 40 years old. METHODS: Different cytoplasmic donation technologies used to rescue aged oocytes with high percentage of aneuploidy were analyzed, and their efficacy compared. MAIN FINDINGS RESULTS: Germinal vesicle transfer (GVT) might be superior to spindle chromosome transfer (ST) theoretically from the point of higher capability of rescuing the disjunction at meiosis I which cannot be helped by ST. However, actually, in vitro maturation (IVM) of oocyte after GVT has not yet been totally completed. ST among other nuclear donations showed the higher possibility to rescue them, due to the fact it does not require in vitro maturation and it has an ethical advantage over pronuclear transfer (PNT) which requires the destruction of an embryo. CONCLUSION: Spindle chromosome transfer has the potential to rescue aged oocytes to some extent, but we have to continue the basic study further to establish the clinical application of cytoplasmic donation to rescue aged oocytes.

Modulating the conformation of the TIR domain by a neoteric MyD88 inhibitor leads to the separation of GVHD from GVT.

Graft-versus-host disease (GVHD) remains the least curable complication after allogeneic bone marrow transplantation (BMT). Myeloid differentiation factor 88 (MyD88) is an adaptor molecule critically involved in the toll-like receptor (TLR) signaling pathway. The Toll/IL-1 receptor (TIR) domains of MyD88 and TLR are interactional modules responsible for sorting and signaling via direct or indirect TIR-TIR interactions, which can contribute to all phases of GVHD progression. Here, we describe the mechanisms of the novel MyD88 inhibitor, TJ-M2010-5, and the discovery of its immunosuppressive properties in the context of GVHD and the graft-versus-tumor (GVT) effect in a fully MHC-mismatched murine model. TJ-M2010-5 potentially interrupted the conformation of the TIR domain through its predicted DD loops, BB loops, and Poc site, and inhibited the homodimerization of MyD88, the LPS-stimulated activation of dendritic cells, and the priming of donor allogeneic T cell proliferation in a dose-dependent manner. Oral administration of TJ-M2010-5 ameliorated the inflammatory environment, decreased the number of apoptotic cells, increased tissue repair in GVHD target organs, and suppressed lethal GVHD. Further, protection against GVHD by TJ-M2010-5 did not abrogate a GVT effect against SP2/0, a myeloma cell line. Our data define the mechanisms of actions and provide novel insight into the potential clinical uses of TJ-M2010-5 for GVHD prevention.

Citrulline malate supplementation does not improve German Volume Training performance or reduce muscle soreness in moderately trained males and females.

BACKGROUND: Use of supplements to aid performance is common practice amongst recreationally active individuals, including those without a sufficient evidence base. This investigation sought to assess whether acute supplementation with 8 g of citrulline malate (CM) (1.11: 1 ratio) would improve anaerobic performance. METHODS: A randomised double blind placebo control trial was employed, using a counterbalanced design. We recruited recreationally active men and women to take part in an isokinetic chair protocol, based on German Volume Training (GVT) whereby participants attempted to perform 10 sets of 10 repetitions against a force representing 70% of their peak concentric force. RESULTS: The number of repetitions achieved over the course of the GVT was 94.0 ± 7.9 and 90.9 ± 13.9 for placebo and CM respectively. There was no significant difference between the placebo and CM treatment for number of repetitions (P = 0.33), isometric (P = 0.60), concentric (P = 0.38), or eccentric (P = 0.65) peak force following the GVT. Total muscle soreness was significantly higher in the CM compared to the placebo treatment following the GVT protocol over 72 h (P = 0.01); although this was not accompanied by a greater workload/number of repetitions in the CM group. CONCLUSIONS: We conclude that an acute dose of CM does not significantly affect anaerobic performance using an isokinetic chair in recreational active participants. Practical implications include precaution in recommending CM supplementation. Coaches and athletes should be aware of the disparity between the chemical analyses of the products reviewed in the present investigation versus the manufacturers' claims.

Grapevine virus T is relatively widespread in Slovakia and Czech Republic and genetically diverse.

A recently described putative foveavirus, grapevine virus T (GVT), was detected in a Slovak grapevine accession (SK704) using high-throughput sequencing, prompting further studies. Full-length genome sequence of isolate GVT-SK704 was determined. Analyses revealed 86.1% nucleotide identity with the Italian GVT isolate, currently the only available nearly complete sequence of GVT in GenBank. A virus-specific RT-PCR assay was developed, which enabled a survey of GVT incidence in grapevine samples from Slovakia and Czech Republic. Unexpectedly, GVT was present in ~ 30% of tested samples. Analysis of complete CP gene sequences of 20 Slovak and Czech GVT isolates detected in the survey revealed relatively high intra-species variability (up to 11.2% nucleotide divergence), suggesting multiple introductions from different sources, possibly over an extended period of time.

Incognito: Are Microchimeric Fetal Stem Cells that Cross Placental Barrier Real Emissaries of Peace?

Chimerism occurs naturaly throughout gestation and can also occur as a consequence of transfusion and transplantation therapy. It consists of the acquisition and long-term persistence of a genetically distinct population of allogenic cells inside another organism. Previous reports have suggested that feto-maternal microchimerism could exert a beneficial effect on the treatment of hematological and solid tumors in patients treated by PBSCT. In this review we report the mechanism of transplacental fetal stem cell trafficking during pregnancy and the effect of their long-term persistence on autoimmunity, GVHD, PBSCT, cancer and stem cell treatment.

Serine protease inhibitor 6 protects alloreactive T cells from Granzyme B-mediated mitochondrial damage without affecting graft-versus-tumor effect.

Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative therapy for hematologic malignancies. Donor T cells are able to eliminate residual tumor cells after allo-HCT, producing the beneficial graft-versus-tumor (GVT) effect, but can also cause graft-versus-host disease (GVHD) when attacking host normal tissues. We previously reported that granzyme B (GzmB) is involved in activation-induced cell death (AICD) of donor T cells and exerts differential impacts on GVHD and GVT effect. Serine protease inhibitor 6 (Spi6) is the sole endogenous inhibitor of GzmB that can protect immune and tissue cells against GzmB-mediated damage. This study is aimed to delineate the mechanism by which the GzmB-Spi6 axis regulates allogeneic T cell response. Using multiple clinically relevant murine allo-HCT models, we have found that Spi6 is concentrated in mitochondria during allogeneic T cell activation, while Spi6-/- T cells exhibit abnormal mitochondrial membrane potential, mass, reactive oxygen species (ROS) production and increased GzmB-dependent AICD mainly in the form of fratricide. Compared with WT T cells, Spi6-/- T cells exhibit decreased expansion in the host and cause significantly reduced GVHD. Notably, however, Spi6-/- T cells demonstrate the same level of GVT activity as WT T cells, which were confirmed by two independent tumor models. In summary, our findings demonstrate that Spi6 plays a novel and critical role in maintaining the integrity of T cell mitochondrial function during allogeneic response, and suggest that disabling Spi6 in donor T cells may represent a novel strategy that can alleviate GVHD without sacrificing the beneficial GVT effect.

Cytotoxic Pathways in Allogeneic Hematopoietic Cell Transplantation.

Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment for hematologic malignancies, and other hematologic and immunologic diseases. Donor-derived immune cells identify and attack cancer cells in the patient producing a unique graft-vs.-tumor (GVT) effect. This beneficial response renders allo-HCT one of the most effective forms of tumor immunotherapy. However, alloreactive donor T cells can damage normal host cells thereby causing graft-vs.-host disease (GVHD), which results in substantial morbidity and mortality. To date, GVHD remains as the major obstacle for more successful application of allo-HCT. Of special significance in this context are a number of cytotoxic pathways that are involved in GVHD and GVT response as well as donor cell engraftment. In this review, we summarize progress in the investigation of these cytotoxic pathways, including Fas/Fas ligand (FasL), perforin/granzyme, and cytokine pathways. Many studies have delineated their distinct operating mechanisms and how they are involved in the complex cellular interactions amongst donor, host, tumor, and infectious pathogens. Driven by progressing elucidation of their contributions in immune reconstitution and regulation, various interventional strategies targeting these pathways have entered translational stages with aims to improve the effectiveness of allo-HCT.

Virotherapy as Potential Adjunct Therapy for Graft-Vs-Host Disease.

PURPOSE OF REVIEW: This review discusses the pathophysiology, risk factors, and the advances in the prevention or treatment of graft-vs-host disease (GvHD) by exploiting adjunct virotherapy. In addition, nonviral adjunct therapeutic options for the prevention of GvHD in the context of allogeneic hematopoietic stem cell transplantation (allo-HSCT) are discussed. The role of oncolytic viruses to treat different HSCT-eligible hematological cancers is also considered and correlated with the issue of GvHD in the context of allo-HSCT. RECENT FINDINGS: Emerging therapies focused on the prevention or treatment of GvHD include the use of regulatory T cells (Tregs), mesenchymal stem cells (MSCs), microbiome manipulation, B cell inhibitors, among others. Our lab and others have reported that an oncolytic DNA virus from the Poxviridae family, called myxoma virus (MYXV), not only exhibits oncolytic activity against various hematologic malignancies like multiple myeloma (MM) or acute myeloid leukemia (AML) but also, in addition, ex vivo MYXV treatment of human allogeneic-bone marrow transplants (allo-BMT), or allo-peripheral blood mononuclear cell (allo-PBMC) transplants can abrogate GvHD in xenografted mice without impairing graft-vs-tumor (GvT) effects against residual cancer. To date, this is the first and the only oncolytic virus with a dual potential of mediating oncolysis against a residual cancer target and also inhibiting or preventing GvHD following allo-HSCT. SUMMARY: This review discusses how oncolytic virotherapy can be applied as a potential adjunct therapy for the potential treatment of GvHD. In addition, we highlight major emerging nonviral therapies currently studied for the treatment or prevention of GvHD. We also review the emerging oncolytic virotherapies against different hematological cancers currently eligible for allo-HSCT and highlight the potential role of the oncolytic virus MYXV to decrease GvHD while maintaining or enhancing the positive benefits of GvT.