GVHD is associated with significant shifts in the composition of the intestinal microbiota in human and mouse models; manipulating the microbiota can alter the severity of GVHD in mice.

Key Points PD-L1 and PD-L2 expression were upregulated during GVHD, whereas PD-1/PD-L1 was more critical than PD-1/PD-L2 in downregulating GVHD. Our data provide new insight into the differential roles of host PD-L1 and PD-L2 and associated mechanisms in controlling GVHD.

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

Dendritic cells (DCs) can be classified into 2 distinct subsets: conventional DCs (cDCs) and plasmacytoid DCs (pDCs). cDCs can prime antigen-specific T-cell immunity, whereas in vivo function of pDCs as antigen-presenting cells remains controversial. We evaluated the contribution of pDCs to allogeneic T-cell responses in vivo in mouse models of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation by an add-back study of MHCexpressing pDCs into major histocompatibility complex-deficient mice that were resistant to GVHD. Alloantigen expression on pDCs alone was sufficient to prime alloreactive T cells and cause GVHD. An inflammatory environment created by host irradiation has the decisive role in maturing pDCs for T-cell priming but this process does not require Toll-like receptor signaling. Thus, functional outcomes of pDC-T-cell interactions depend on the immunologic context of encounter. To our knowledge, these results are the first to directly demonstrate an in vivo pathogenic role of pDCs as antigenpresenting cells in an antigen-specific T cell-mediated disease in the absence of other DC subsets and to provide important insight into developing strategies for tolerance induction in transplantation. IntroductionThe interaction of naive T cells and dendritic cells (DCs) is essential for initiating primary immune responses. DCs can be divided into 2 distinct subsets: conventional DCs (cDCs) and plasmacytoid DCs (pDCs) according to their immunophenotype and functional properties. 1-3 pDCs represent a CD11c int B220 ϩ DC subset that differs from the CD11c high B220 Ϫ major histocompatibility complex (MHC) class II high cDCs, commonly viewed as the classic stimulators of naive T cells. One distinctive feature of pDCs is their capacity to rapidly produce high levels of type I interferon (IFN) in response to viral and bacterial stimuli, highlighting the importance of pDCs in innate immune responses. 2-8 pDCs express low levels of surface MHC and classical costimulatory molecules; therefore, they are poor T-cell stimulators. [5][6][7][8][9][10][11] In contrast, pDCs matured with CD40 ligands or Toll-like receptor (TLR) ligands are potent antigen-presenting cells (APCs), capable of stimulating naive T-cell proliferation and differentiation to helper, killer, memory, and regulatory T cells in vitro. 7,12,13 In vivo, injection of pDCs activated by synthetic oligodeoxynucleotides containing unmethylated cytosine-guanine motifs (CpG), but not immature pDCs, is capable of eliciting antigen-specific CD8 ϩ T-cell responses. 10,14 On the other hand, OVA-pulsed pDCs protected mice against OVA-induced asthma development. 15 pDCs in the tumordraining lymph nodes express indole 2, 3-dioxygenase, and suppress antitumor T-cell responses. 16 In patients with ovarian cancer, large numbers of pDCs, which induced interleukin 10 (IL10)-producing regulatory T cells, were found in ascites. 17 pDCs mediate tolerance and prolong survival of cardiac allografts. 11,18,19 Several recent clinical observations...

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• Expression and function of vitamin A metabolizing enzymes are increased in the intestine and mesenteric lymph nodes during GVHD.• Inhibiting donor T-cell RAR signaling reduces Th1 differentiation, gut homing, and GVHD while preserving graft-versus-lymphoma effects.Graft-versus-host disease (GVHD) is a critical complication after allogeneic bone marrow transplantation. During GVHD, donor T cells are activated by host antigen-presenting cells and differentiate into T-effector cells (Teffs) that migrate to GVHD target organs. However, local environmental factors influencing Teff differentiation and migration are largely unknown. Vitamin A metabolism within the intestine produces retinoic acid, which contributes to intestinal homeostasis and tolerance induction. Here, we show that the expression and function of vitamin A-metabolizing enzymes were increased in the intestine and mesenteric lymph nodes in mice with active GVHD. Moreover, transgenic donor T cells expressing a retinoic acid receptor (RAR) response element luciferase reporter responded to increased vitamin A metabolites in GVHD-affected organs. Increasing RAR signaling accelerated GVHD lethality, whereas donor T cells expressing a dominant-negative RARa (dnRARa) showed markedly diminished lethality. The dnRARa transgenic T cells showed reduced Th1 differentiation and a4b7 and CCR9 expression associated with poor intestinal migration, low GVHD pathology, and reduced intestinal permeability, primarily via CD4 1 T cells. The inhibition of RAR signaling augmented donor-induced Treg generation and expansion in vivo, while preserving graft-versus-leukemia effects. Together, these results suggested that reagents blunting donor T-cell RAR signaling may possess therapeutic anti-GVHD properties. (Blood. 2013; 122(12):2125-2134

Exposure of offspring to noninherited maternal antigens (NIMAs) during pregnancy may have an impact on transplantations performed later in life. Using a mouse model, we recently showed that bone marrow transplantation (BMT) from NIMA-exposed offspring to the mother led to a reduction of graft-versus-host disease (GVHD). Since offspring can also be exposed to NIMAs by breastfeeding after birth, we tested whether breast milk could mediate the tolerogenic NIMA effect. We found that oral exposure to NIMAs by breastfeeding alone was sufficient to reduce GVHD, and that in utero exposure to NIMAs is required for maximum reduction of GVHD. The tolerogenic milk effects disappeared when donor mice were injected with CD25 monoclonal antibodies during the lactation period, suggesting a CD4 ؉ CD25 ؉ regulatory T celldependent mechanism. Our results suggest a previously unknown impact of breastfeeding on the outcome of transplantation. (Blood. 2009;113:1829-1833) IntroductionAllogeneic hematopoietic stem cell transplantation (HSCT) is a potential curative treatment for malignant hematologic diseases; however, HSCT from haploidentical-related donors is complicated by a high incidence of severe graft-versus-host disease (GVHD).The fetus and mother must tolerate each other's alloantigens during pregnancy. Fetal and maternal antigens transmitted through the bidirectional transplacental passage during pregnancy might induce tolerance to noninherited maternal antigens (NIMAs) in the offspring and inherited paternal antigens (IPAs) in the mother. [1][2][3][4] Exposure of the fetus to allogeneic cells may induce a long-lasting tolerance specific to the alloantigens of the donor cells. 5,6 We recently demonstrated using a mouse model that a "child-tomother" bone marrow transplantation (BMT) from a NIMAexposed donor reduces the mortality and morbidity of GVHD, but a "mother-to-child" BMT from a mother donor exposed to IPAs from the fetus does not. 7 We therefore tested the hypothesis that breastfeeding plays an important role in the buildup of the tolerogenic NIMA effect in a mouse model of a "child-to-mother" BMT because breast milk is rich in maternal major histocompatibility complex (MHC) antigens in both soluble and cellular forms. 8-11 Methods MiceFemale C57BL/6 (B6, H-2 b/b ) and B6D2F1 (H-2 b/d ) mice were purchased from Charles River Japan (Yokohama, Japan). B6D1F1 (H-2 b/q ) mice were produced by mating a DBA/1 (H-2 q ) female (Japan SLC, Shizuoka, Japan) and a B6 male. NIMA-exposed H-2 b mice were produced by mating a B6 (H-2 b ) male and a B6D2F1 (H-2 b/d ) female as previously described. 7,9,12 Offspring were typed for the H-2 locus by flow cytometry using monoclonal antibodies (mAbs) specific for H-2K b and H-2K d (BD Pharmingen, San Diego, CA) as previously described. 7 The resultant H-2 b/b offspring were nursed by either a B6D2F1 mother (NIMA [in utero ϩ oral]) or a B6 foster mother (NIMA [in utero]). Controls were H-2 b mice not exposed to H-2 d . To produce NIMA-exposed mice via breastfeeding, B6 neonates were nursed ...

The ACA index has the ability to stratify the prognosis, tolerability to cytotoxic drugs, and adherence to treatment of elderly patients with DLBCL treated with R-CHOP. 2017;22:554-560 IMPLICATIONS FOR PRACTICE: Currently, little is known regarding how to identify elderly patients with diffuse large B-cell lymphoma who may tolerate a full dose of chemotherapy or to what extent cytotoxic drugs should be reduced in some specific conditions. The Society of Lymphoma Treatment in Japan developed a host-dependent prognostic model consisting of higher age (>75 years), hypoalbuminemia (<3.7 g/dL), and higher Charlson Comorbidity Index score (≥3) for such elderly patients. This model can stratify the prognosis, tolerability to cytotoxic drugs, and adherence to treatment of these patients and thus help clinicians in formulating personalized treatment strategies for this growing patient population.