Browsing by Author "Reddy, Pavan"

Now showing 1 - 8 of 8
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    Allogeneic T cells cause acute renal injury after hematopoietic cell transplantation
    (American Society of Hematology, 2023) Miyata, Masahiro; Matsuki, Eri; Ichikawa, Kazunobu; Takehara, Tomohiro; Hosokawa, Yuka; Sekiguchi, Erika; Peltier, Daniel; Reddy, Pavan; Ishizawa, Kenichi; Watanabe, Masafumi; Toubai, Tomomi; Pediatrics, School of Medicine
    Acute kidney injury (AKI) is a frequent complication of allogeneic hematopoietic cell transplantation (allo-HCT). There are many causes of AKI after allo-HCT, but it is unknown whether renal acute graft-versus-host disease (aGVHD) caused by direct allogeneic donor T-cell-mediated renal damage contributes. Here, we tested whether allogeneic donor T cells attack kidneys in murine models of aGVHD. To avoid confounding effects of nephrotoxic agents, we did not administer immunosuppressants for GVHD prophylaxis. We found that urinary N-acetyl-β-D-glucosaminidase, a marker of tubular injury, was elevated in allogeneic recipients on day 14 after allogeneic bone marrow transplantation. Donor major histocompatibility complex-positive cells were present and CD3+ T cells were increased in the glomerulus, peritubular capillaries, interstitium, and perivascular areas in the kidneys of allo-HCT recipient mice. These T cells included both CD4+ and CD8+ cells with elevated activation markers, increased exhaustion markers, and greater secretion of proinflammatory cytokines and cytotoxic proteins. Consistent with allo-T-cell-mediated renal damage, expression of neutrophil gelatinase-binding lipocalin, a marker of AKI, and elafin, a marker of aGVHD, were increased in renal tissue of allogeneic recipients. Because apoptosis of target cells is observed on histopathology of aGVHD target tissues, we confirmed that alloreactive T cells increased apoptosis of renal endothelial and tubular epithelial cells in cytotoxic T-lymphocyte assays. These data suggest that immune responses induced by donor T cells contribute to renal endothelial and tubular epithelial cell injury in allo-HCT recipients and that aGVHD may contribute to AKI after allo-HCT.
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    ATG5-Dependent Autophagy Uncouples T-cell Proliferative and Effector Functions and Separates Graft-versus-Host Disease from Graft-versus-Leukemia
    (American Association for Cancer Research, 2021) Oravecz-Wilson, Katherine; Rossi, Corinne; Zajac, Cynthia; Sun, Yaping; Li, Lu; Decoville, Thomas; Fujiwara, Hideaki; Kim, Stephanie; Peltier, Daniel; Reddy, Pavan; Medicine, School of Medicine
    Autophagy is a vital cellular process whose role in T immune cells is poorly understood, specifically, in its regulation of allo-immunity. Stimulation of wild-type T cells in vitro and in vivo with allo-antigens enhances autophagy. To assess the relevance of autophagy to T-cell allo-immunity, we generated T-cell-specific Atg5 knock-out mice. Deficiency of ATG5-dependent autophagy reduced T-cell proliferation and increased apoptosis following in vitro and in vivo allo-stimulation. The absence of ATG5 in allo-stimulated T cells enhanced their ability to release effector cytokines and cytotoxic functions, uncoupling their proliferation and effector functions. Absence of autophagy reduced intracellular degradation of cytotoxic enzymes such as granzyme B, thus enhancing the cytotoxicity of T cells. In several in vivo models of allo-HSCT, ATG5-dependent dissociation of T-cell functions contributed to significant reduction in graft-versus-host disease (GVHD) but retained sufficient graft versus tumor (GVT) response. Our findings demonstrate that ATG5-dependent autophagy uncouples T-cell proliferation from its effector functions and offers a potential new strategy to enhance outcomes after allo-HSCT. SIGNIFICANCE: These findings demonstrate that induction of autophagy in donor T-cell promotes GVHD, while inhibition of T-cell autophagy mitigates GVHD without substantial loss of GVL responses.
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    LNCing RNA to Imm
    (Elsevier, 2022) Peltier, Daniel C.; Roberts, Alexis; Reddy, Pavan; Pediatrics, School of Medicine
    Despite an ever-increasing appreciation of how protein-coding genes shape immune responses, the molecular underpinnings of immune regulation remain incompletely understood. This incomplete picture impedes the development of more precise therapeutics and diagnostics for immune-mediated diseases. Long noncoding RNAs (lncRNAs) are versatile cell- and context-specific regulators of gene expression and cellular function. The number of lncRNA genes rivals that of protein-coding genes; however, comparatively little is known about their function. Even though the functions of most lncRNA genes are unknown, multiple lncRNAs have recently emerged as important immune regulators. Therefore, further unlocking the role of lncRNAs in the mammalian immune system coupled with their tissue-specific expression might lead to more precise therapeutics and diagnostics for immune disorders in general.
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    Mitochondrial Complex II In Intestinal Epithelial Cells Regulates T-cell Mediated Immunopathology
    (Springer Nature, 2021) Fujiwara, Hideaki; Seike, Keisuke; Brooks, Michael D.; Mathew, Anna V.; Kovalenko, Ilya; Pal, Anupama; Lee, Ho-Joon; Peltier, Daniel; Kim, Stephanie; Liu, Chen; Oravecz-Wilson, Katherine; Li, Lu; Sun, Yaping; Byun, Jaeman; Maeda, Yoshinobu; Wicha, Max S.; Saunders, Tom; Rehemtulla, Alnawaz; Lyssiotis, Costas A.; Pennathur, Subramaniam; Reddy, Pavan; Microbiology and Immunology, School of Medicine
    Intestinal epithelial cell (IEC) damage by T cells contributes to graft-versus-host disease (GVHD), inflammatory bowel disease (IBD) and immune checkpoint blockade (ICB) mediated colitis. But little is known about the target cell intrinsic features that influence disease severity. Herein we identified disruption of oxidative phosphorylation and an increase in succinate levels in the IECs from several distinct in vivo models of T cell mediated colitis. Metabolic flux studies, complemented by imaging and protein analyses identified disruption of IEC intrinsic succinate dehydrogenase A (SDHA), a component of mitochondrial complex II, in causing these metabolic alterations. The relevance of IEC intrinsic SDHA in mediating disease severity was confirmed by complementary chemical and genetic experimental approaches and validated in human clinical samples. These data identify a critical role for the alteration of the IEC specific mitochondrial complex II component SDHA in the regulation of the severity of T cell mediated intestinal diseases.
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    Oral inflammation and microbiome dysbiosis exacerbate chronic graft-versus-host disease
    (American Society of Hematology, 2025) Kambara, Yui; Fujiwara, Hideaki; Yamamoto, Akira; Gotoh, Kazuyoshi; Tsuji, Shuma; Kunihiro, Mari; Oyama, Tadashi; Terao, Toshiki; Sato, Ayame; Tanaka, Takehiro; Peltier, Daniel; Seike, Keisuke; Nishimori, Hisakazu; Asada, Noboru; Ennishi, Daisuke; Fujii, Keiko; Fujii, Nobuharu; Matsuoka, Ken-Ichi; Soga, Yoshihiko; Reddy, Pavan; Maeda, Yoshinobu; Pediatrics, School of Medicine
    The oral microbiota, second in abundance to the gut, is implicated in chronic systemic diseases, but its specific role in graft-versus-host disease (GVHD) pathogenesis has been unclear. Our study finds that mucositis-induced oral dysbiosis in patients after hematopoietic cell transplantation (HCT) associated with increased chronic GVHD (cGVHD), even in patients receiving posttransplant cyclophosphamide. In murine HCT models, oral dysbiosis caused by bilateral molar ligatures exacerbated cGVHD and increased bacterial load in the oral cavity and gut, with Enterococcaceae significantly increasing in both organs. In this model, the migration of Enterococcaceae to cervical lymph nodes both before and after transplantation activated antigen-presenting cells, thereby promoting the expansion of donor-derived inflammatory T cells. Based on these results, we hypothesize that pathogenic bacteria increase in the oral cavity might not only exacerbate local inflammation but also enhance systemic inflammation throughout the HCT course. Additionally, these bacteria translocated to the gut and formed ectopic colonies, further amplifying systemic inflammation. Furthermore, interventions targeting the oral microbiome mitigated murine cGVHD. Collectively, our findings highlight the importance of oral dysbiosis in cGVHD and suggest that modulation of the oral microbiome during transplantation may be an effective approach for preventing or treating cGVHD.
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    Rearrangement of T Cell genome architecture regulates GVHD
    (Elsevier, 2022-08-06) Sun, Yaping; Dotson, Gabrielle A.; Muir, Lindsey A.; Ronquist, Scott; Oravecz-Wilson, Katherine; Peltier, Daniel; Seike, Keisuke; Li, Lu; Meixner, Walter; Rajapakse, Indika; Reddy, Pavan; Pediatrics, School of Medicine
    WAPL, cohesin's DNA release factor, regulates three-dimensional (3D) chromatin architecture. The 3D chromatin structure and its relevance to mature T cell functions is not well understood. We show that in vivo lymphopenic expansion, and alloantigen-driven proliferation, alters the 3D structure and function of the genome in mature T cells. Conditional deletion of WAPL, cohesin's DNA release factor, in T cells reduced long-range genomic interactions and altered chromatin A/B compartments and interactions within topologically associating domains (TADs) of the chromatin in T cells at baseline. WAPL deficiency in T cells reduced loop extensions, changed expression of cell cycling genes and reduced proliferation following in vitro and in vivo stimulation, and reduced severity of graft-versus-host disease (GVHD) following experimental allogeneic hematopoietic stem cell transplantation. These data collectively characterize 3D genomic architecture of T cells in vivo and demonstrate biological and clinical implications for its disruption by cohesin release factor WAPL.
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    RNA-seq of Human T Cells after Hematopoietic Stem Cell Transplantation Identifies Linc00402 as a Regulator of T-Cell Alloimmunity
    (American Association for the Advancement of Science, 2021) Peltier, Daniel; Radosevich, Molly; Ravikumar, Visweswaran; Pitchiaya, Sethuramasundaram; Decoville, Thomas; Wood, Sherri C.; Hou, Guoqing; Zajac, Cynthia; Oravecz-Wilson, Katherine; Sokol, David; Henig, Israel; Wu, Julia; Kim, Stephanie; Taylor, Austin; Fujiwara, Hideaki; Sun, Yaping; Rao, Arvind; Chinnaiyan, Arul M.; Goldstein, Daniel R.; Reddy, Pavan; Pediatrics, School of Medicine
    Mechanisms governing allogeneic T cell responses after solid organ and allogeneic hematopoietic stem cell transplantation (HSCT) are incompletely understood. To identify lncRNAs that regulate human donor T cells after clinical HSCT, we performed RNA sequencing on T cells from healthy individuals and donor T cells from three different groups of HSCT recipients that differed in their degree of major histocompatibility complex (MHC) mismatch. We found that lncRNA differential expression was greatest in T cells after MHC-mismatched HSCT relative to T cells after either MHC-matched or autologous HSCT. Differential expression was validated in an independent patient cohort and in mixed lymphocyte reactions using ex vivo healthy human T cells. We identified Linc00402, an uncharacterized lncRNA, among the lncRNAs differentially expressed between the mismatched unrelated and matched unrelated donor T cells. We found that Linc00402 was conserved and exhibited an 88-fold increase in human T cells relative to all other samples in the FANTOM5 database. Linc00402 was also increased in donor T cells from patients who underwent allogeneic cardiac transplantation and in murine T cells. Linc00402 was reduced in patients who subsequently developed acute graft-versus-host disease. Linc00402 enhanced the activity of ERK1 and ERK2, increased FOS nuclear accumulation, and augmented expression of interleukin-2 and Egr-1 after T cell receptor engagement. Functionally, Linc00402 augmented the T cell proliferative response to an allogeneic stimulus but not to a nominal ovalbumin peptide antigen or polyclonal anti-CD3/CD28 stimulus. Thus, our studies identified Linc00402 as a regulator of allogeneic T cell function.
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    ST2 as a Marker for Risk of Therapy-Resistant Graft-versus-Host Disease and Death
    (Massachusetts Medical Society, 2013) Vander Lugt, Mark T.; Braun, Thomas M.; Hanash, Samir; Ritz, Jerome; Ho, Vincent T.; Antin, Joseph H.; Zhang, Qing; Wong, Chee-Hong; Wang, Hong; Chin, Alice; Gomez, Aurélie; Harris, Andrew C.; Levine, John E.; Choi, Sung W.; Couriel, Daniel; Reddy, Pavan; Ferrara, James L. M.; Paczesny, Sophie; Pediatrics, School of Medicine
    Background: No plasma biomarkers are associated with the response of acute graft-versus-host disease (GVHD) to therapy after allogeneic hematopoietic stem-cell transplantation. Methods: We compared 12 biomarkers in plasma obtained a median of 16 days after therapy initiation from 10 patients with a complete response by day 28 after therapy initiation and in plasma obtained from 10 patients with progressive GVHD during therapy. The lead biomarker, suppression of tumorigenicity 2 (ST2), was measured at the beginning of treatment for GVHD in plasma from 381 patients and during the first month after transplantation in three independent sets totaling 673 patients to determine the association of this biomarker with treatment-resistant GVHD and 6-month mortality after treatment or transplantation. Results: Of the 12 markers, ST2 had the most significant association with resistance to GVHD therapy and subsequent death without relapse. As compared with patients with low ST2 values at therapy initiation, patients with high ST2 values were 2.3 times as likely to have treatment-resistant GVHD (95% confidence interval [CI], 1.5 to 3.6) and 3.7 times as likely to die within 6 months after therapy (95% CI, 2.3 to 5.9). Patients with low ST2 values had lower mortality without relapse than patients with high ST2 values, regardless of the GVHD grade (11% vs. 31% among patients with grade I or II GVHD and 14% vs. 67% among patients with grade III or IV GVHD, P<0.001 for both comparisons). Plasma ST2 values at day 14 after transplantation were associated with 6-month mortality without relapse, regardless of the intensity of the conditioning regimen. Conclusions: ST2 levels measured at the initiation of therapy for GVHD and during the first month after transplantation improved risk stratification for treatment-resistant GVHD and death without relapse after transplantation.