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      Targeting Cytokines in GVHD Therapy

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          Abstract

          Transplantation of donor-derived allogeneic hematopoietic cells causes increased survival in patients suffering from various blood cancers and other hematologic and immunologic diseases. However, this health benefit is limited to certain patients. One major complication is graft-versus-host disease (GVHD) that occurs when donor-derived immune cells recognize host cells/tissues as foreign and perpetrate subsequent destruction. Cytokines are a major class of effector molecules that are involved in GVHD pathogenesis. Proinflammatory cytokines released by activated immune cells including T cells lead to the onset of GVHD. T cell depletion (TCD) is an effective approach for GVHD prevention. Several immune suppressive drugs are also used to treat GVHD. However, these prophylactic and treatment strategies often lead to an immune compromised state that increases the risk for infection and cancer relapse. Considering the adverse effects of TCD and overall immune suppression, more selective managements such as approaches targeting proinflammatory cytokines have emerged as a promising strategy to control GVHD. Therefore, this work is dedicated to review recent development in the studies of cytokines and their future implication in GVHD therapy.

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          Interleukin-22 protects intestinal stem cells from immune-mediated tissue damage and regulates sensitivity to graft versus host disease.

          Little is known about the maintenance of intestinal stem cells (ISCs) and progenitors during immune-mediated tissue damage or about the susceptibility of transplant recipients to tissue damage mediated by the donor immune system during graft versus host disease (GVHD). We demonstrate here that deficiency of recipient-derived IL-22 increased acute GVHD tissue damage and mortality, that ISCs were eliminated during GVHD, and that ISCs as well as their downstream progenitors expressed the IL-22 receptor. Intestinal IL-22 was produced after bone marrow transplant by IL-23-responsive innate lymphoid cells (ILCs) from the transplant recipients, and intestinal IL-22 increased in response to pretransplant conditioning. However, ILC frequency and IL-22 amounts were decreased by GVHD. Recipient IL-22 deficiency led to increased crypt apoptosis, depletion of ISCs, and loss of epithelial integrity. Our findings reveal IL-22 as a critical regulator of tissue sensitivity to GVHD and a protective factor for ISCs during inflammatory intestinal damage. Copyright © 2012 Elsevier Inc. All rights reserved.
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            Low-dose interleukin-2 therapy restores regulatory T cell homeostasis in patients with chronic graft-versus-host disease.

            CD4(+)Foxp3(+) regulatory T cells (Tregs) play a central role in the maintenance of immune tolerance after allogeneic hematopoietic stem cell transplantation. We recently reported that daily administration of low-dose interleukin-2 (IL-2) induces selective expansion of functional Tregs and clinical improvement of chronic graft-versus-host disease (GVHD). To define the mechanisms of action of IL-2 therapy, we examined the immunologic effects of this treatment on homeostasis of CD4(+) T cell subsets after transplant. We first demonstrated that chronic GVHD is characterized by constitutive phosphorylation of signal transducer and activator of transcription 5 (Stat5) in conventional CD4(+) T cells (Tcons) associated with elevated amounts of IL-7 and IL-15 and relative functional deficiency of IL-2. IL-2 therapy resulted in the selective increase of Stat5 phosphorylation in Tregs and a decrease of phosphorylated Stat5 in Tcons. Over an 8-week period, IL-2 therapy induced a series of changes in Treg homeostasis, including increased proliferation, increased thymic export, and enhanced resistance to apoptosis. Low-dose IL-2 had minimal effects on Tcons. These findings define the mechanisms whereby low-dose IL-2 therapy restores the homeostasis of CD4(+) T cell subsets and promotes the reestablishment of immune tolerance.
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              Interleukin 15: biology and relevance to human disease.

              T Fehniger (2001)
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                Author and article information

                Journal
                101692820
                45740
                J Immunol Res Ther
                J Immunol Res Ther
                Journal of immunology research and therapy
                2472-727X
                12 July 2017
                28 June 2017
                2017
                15 August 2017
                : 2
                : 1
                : 90-99
                Affiliations
                [1 ]Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
                Author notes
                Corresponding author: Xuefang Cao, MD, PhD, Department of Immunology, Roswell Park Cancer Institute Elm and Carlton Streets, Buffalo, NY 14263, USA, Tel: (716) 845-3963; Fax: (716) 845-1322; Xuefang.Cao@ 123456RoswellPark.org
                [2]

                Current address: Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, Chicago, IL 60612, USA

                Article
                NIHMS891689
                5557058
                28819653
                de250d6d-7ec6-4a60-a29c-abb4053cb714

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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                Article

                hematopoietic cell transplantation,graft-versus-host disease,t cells,cytokines

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