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Rejection of iPS cells Induced pluripotent stem (iPS) cells, which are produced by reprogramming fully differentiated adult cells back to an embryonic-like state by expression of specific genes, have important therapeutic potential. As iPS cells are derived entirely from the patient, one hoped-for advantage of using them in therapy is that there should be no immune rejection. Now it seems this might not be the case. In experiments in which iPS cells were reprogrammed using a retroviral or non-integrative episomal approach and then transplanted into mice, teratoma cells derived from the iPS cells were rejected by the immune system, even in syngeneic recipients. This finding suggests that altered gene expression in some cells differentiated from iPS cells can induce T-cell-dependent immune responses. The authors suggest that the immunogenicity of therapeutically valuable cells derived from patient-specific iPS cells should be evaluated before they are used in any clinical applications. Induced pluripotent stem cells (iPSCs), reprogrammed from somatic cells with defined factors, hold great promise for regenerative medicine as the renewable source of autologous cells 1 , 2 , 3 , 4 , 5 . Whereas it has been generally assumed that these autologous cells should be immune-tolerated by the recipient from whom the iPSCs are derived, their immunogenicity has not been vigorously examined. We show here that, whereas embryonic stem cells (ESCs) derived from inbred C57BL/6 (B6) mice can efficiently form teratomas in B6 mice without any evident immune rejection, the allogeneic ESCs from 129/SvJ mice fail to form teratomas in B6 mice due to rapid rejection by recipients. B6 mouse embryonic fibroblasts (MEFs) were reprogrammed into iPSCs by either retroviral approach (ViPSCs) or a novel episomal approach (EiPSCs) that causes no genomic integration. In contrast to B6 ESCs, teratomas formed by B6 ViPSCs were mostly immune-rejected by B6 recipients. In addition, the majority of teratomas formed by B6 EiPSCs were immunogenic in B6 mice with T cell infiltration, and apparent tissue damage and regression were observed in a small fraction of teratomas. Global gene expression analysis of teratomas formed by B6 ESCs and EiPSCs revealed a number of genes frequently overexpressed in teratomas derived from EiPSCs, and several such gene products were shown to contribute directly to the immunogenicity of the B6 EiPSC-derived cells in B6 mice. These findings indicate that, in contrast to derivatives of ESCs, abnormal gene expression in some cells differentiated from iPSCs can induce T-cell-dependent immune response in syngeneic recipients. Therefore, the immunogenicity of therapeutically valuable cells derived from patient-specific iPSCs should be evaluated before any clinic application of these autologous cells into the patients.

Five patients with end-stage renal disease received bone marrow and kidney transplants from HLA-mismatched living related donors. Transient hematopoietic chimerism developed in all five. In one patient, irreversible humoral rejection occurred. In the other four recipients, immunosuppressive therapy was discontinued after 9 to 14 months and renal function has subsequently remained stable. Five patients with end-stage renal disease received bone marrow and kidney transplants from HLA-mismatched living related donors. In four recipients, immunosuppressive therapy was discontinued after 9 to 14 months and renal function has subsequently remained stable. Long-term results of organ transplantation remain unsatisfactory, mainly because of chronic rejection and complications associated with immunosuppressive medications. 1 , 2 Immune tolerance, which has been achieved in animal models, might provide a means for avoiding both of these problems. However, the results of attempts to extend such studies from laboratory animals to humans have been disappointing. 3 – 7 Tolerance of allografts has been induced in mice 8 and larger animals 9 by first transplanting hematopoietic stem cells from the prospective donor into the recipient, thereby creating a lymphohematopoietic chimera in which donor and recipient hematopoiesis coexist (“mixed chimera”). Using a nonmyeloablative perioperative regimen, we . . .

A privileged position A new study identifies the bone marrow haematopoietic stem cell (HSC) niche — a specialized microenvironment where stem cells reside — as an immune privileged site. This property is known to exist in the testis, ovary and hair follicle but has not been universally demonstrated in all stem cell niches. High-resolution in vivo imaging shows the accumulation of regulatory T cells in the HSC niche, enabling transplanted allo-HSCs to escape from allogeneic rejection. As well as supporting stem-cell function, the niche may provide a relative sanctuary from immune attack that could extend to malignant cells in some instances. Stem cells reside in a specialized regulatory microenvironment or niche 1 , 2 , where they receive appropriate support for maintaining self-renewal and multi-lineage differentiation capacity 1 , 2 , 3 . The niche may also protect stem cells from environmental insults 3 including cytotoxic chemotherapy and perhaps pathogenic immunity 4 . The testis, hair follicle and placenta are all sites of residence for stem cells and are immune-suppressive environments, called immune-privileged sites, where multiple mechanisms cooperate to prevent immune attack, even enabling prolonged survival of foreign allografts without immunosuppression 4 . We sought to determine if somatic stem-cell niches more broadly are immune-privileged sites by examining the haematopoietic stem/progenitor cell (HSPC) niche 1 , 2 , 5 , 6 , 7 in the bone marrow, a site where immune reactivity exists 8 , 9 . We observed persistence of HSPCs from allogeneic donor mice (allo-HSPCs) in non-irradiated recipient mice for 30 days without immunosuppression with the same survival frequency compared to syngeneic HSPCs. These HSPCs were lost after the depletion of FoxP3 regulatory T (T reg ) cells. High-resolution in vivo imaging over time demonstrated marked co-localization of HSPCs with T reg cells that accumulated on the endosteal surface in the calvarial and trabecular bone marrow. T reg cells seem to participate in creating a localized zone where HSPCs reside and where T reg cells are necessary for allo-HSPC persistence. In addition to processes supporting stem-cell function, the niche will provide a relative sanctuary from immune attack.

To investigate if recurrent autoimmunity explained hyperglycemia and C-peptide loss in three immunosuppressed simultaneous pancreas-kidney (SPK) transplant recipients. We monitored autoantibodies and autoreactive T-cells (using tetramers) and performed biopsy. The function of autoreactive T-cells was studied with in vitro and in vivo assays. Autoantibodies were present pretransplant and persisted on follow-up in one patient. They appeared years after transplantation but before the development of hyperglycemia in the remaining patients. Pancreas transplant biopsies were taken within approximately 1 year from hyperglycemia recurrence and revealed beta-cell loss and insulitis. We studied autoreactive T-cells from the time of biopsy and repeatedly demonstrated their presence on further follow-up, together with autoantibodies. Treatment with T-cell-directed therapies (thymoglobulin and daclizumab, all patients), alone or with the addition of B-cell-directed therapy (rituximab, two patients), nonspecifically depleted T-cells and was associated with C-peptide secretion for >1 year. Autoreactive T-cells with the same autoantigen specificity and conserved T-cell receptor later reappeared with further C-peptide loss over the next 2 years. Purified autoreactive CD4 T-cells from two patients were cotransplanted with HLA-mismatched human islets into immunodeficient mice. Grafts showed beta-cell loss in mice receiving autoreactive T-cells but not control T-cells. We demonstrate the cardinal features of recurrent autoimmunity in three such patients, including the reappearance of CD4 T-cells capable of mediating beta-cell destruction. Markers of autoimmunity can help diagnose this underappreciated cause of graft loss. Immune monitoring during therapy showed that autoimmunity was not resolved by the immunosuppressive agents used.

Mature donor T cells cause graft-versus-host disease (GVHD), but they are also the main mediators of the beneficial graft-versus-tumor (GVT) activity of allogeneic bone marrow transplantation. Suppression of GVHD with maintenance of GVT activity is a desirable outcome for clinical transplantation. We have previously shown that donor-derived CD4 + CD25 + regulatory T cells inhibit lethal GVHD after allogeneic bone marrow transplantation across major histocompatibility complex (MHC) class I and II barriers in mice. Here we demonstrate that in host mice with leukemia and lymphoma, CD4 + CD25 + regulatory T cells suppress the early expansion of alloreactive donor T cells, their interleukin-2-receptor (IL-2R) α-chain expression and their capacity to induce GVHD without abrogating their GVT effector function, mediated primarily by the perforin lysis pathway. Thus, CD4 + CD25 + T cells are potent regulatory cells that can separate GVHD from GVT activity mediated by conventional donor T cells.

Contrary to the proinflammatory role of mast cells in allergic disorders, the results obtained in this study establish that mast cells are essential in CD4 + CD25 + Foxp3 + regulatory T (T Reg )-cell-dependent peripheral tolerance. Here we confirm that tolerant allografts, which are sustained owing to the immunosuppressive effects of T Reg cells, acquire a unique genetic signature dominated by the expression of mast-cell-gene products. We also show that mast cells are crucial for allograft tolerance, through the inability to induce tolerance in mast-cell-deficient mice. High levels of interleukin (IL)-9—a mast cell growth and activation factor—are produced by activated T Reg cells, and IL-9 production seems important in mast cell recruitment to, and activation in, tolerant tissue. Our data indicate that IL-9 represents the functional link through which activated T Reg cells recruit and activate mast cells to mediate regional immune suppression, because neutralization of IL-9 greatly accelerates allograft rejection in tolerant mice. Finally, immunohistochemical analysis clearly demonstrates the existence of this novel T Reg –IL-9–mast cell relationship within tolerant allografts. Mast Cells and Graft Rejection Mast cells are important immune system components, best known as responders in allergic reactions such as anaphylaxis and asthma. Recent work suggests that they also act as immunoregulatory cells in both innate and adaptive immunity and surprisingly, gene expression profiles point to an association with tolerance to tissue transplants. Studies in mice now confirm that mast cells are major cellular players in immune suppression, needed for peripheral suppression dependent on regulatory T cells. This also implies a role for interleukin 9 (IL-9) as a link between activated T cells and mast cell recruitment and makes IL-9, mast cells and their gene products of interest as targets for drugs to prevent graft rejection.

Tregs play a pivotal role in inducing and maintaining donor-specific transplant tolerance. The T cell immunoglobulin and mucin domain-3 protein (TIM-3) is expressed on many fully activated effector T cells. Along with program death 1 (PD-1), TIM-3 is used as a marker for exhausted effector T cells, and interaction with its ligand, galectin-9, leads to selective death of TIM-3+ cells. We report herein the presence of a galectin-9-sensitive CD4+FoxP3+TIM-3+ population of T cells, which arose from CD4+FoxP3+TIM-3- proliferating T cells in vitro and in vivo and were often PD-1+. These cells became very prominent among graft-infiltrating Tregs during allograft response. The frequency and number of TIM-3+ Tregs peaked at the time of graft rejection and declined thereafter. Moreover, these cells also arise in a tolerance-promoting donor-specific transfusion model, representing a pool of proliferating, donor-specific Tregs. Compared with TIM-3- Tregs, TIM-3+ Tregs, which are often PD-1+ as well, exhibited higher in vitro effector function and more robust expression of CD25, CD39, CD73, CTLA-4, IL-10, and TGF-β but not galectin-9. However, these TIM-3+ Tregs did not flourish when passively transferred to newly transplanted hosts. These data suggest that a heretofore unrecognized graft-infiltrating, short-lived subset of Tregs can restrain rejection.

Mesenchymal Stem Cells Prevent the Rejection of Fully Allogenic Islet Grafts by the Immunosuppressive Activity of Matrix Metalloproteinase-2 and -9 Yunchuan Ding 1 , Danmei Xu 2 , Gang Feng 1 , Andrew Bushell 1 , Ruth J. Muschel 2 and Kathryn J. Wood 1 1 Transplantation Research Immunology Group, Nuffield Department of Surgery, University of Oxford, John Radcliffe Hospital, Oxford, U.K.; 2 Department of Radiation Oncology and Biology, Radiobiology Research Institute, University of Oxford, Oxford, U.K. Corresponding author: Yunchuan Ding, yunchuan.ding{at}nds.ox.ac.uk . Y.D. and D.X. contributed equally to this article. Abstract OBJECTIVE Mesenchymal stem cells (MSCs) are known to be capable of suppressing immune responses, but the molecular mechanisms involved and the therapeutic potential of MSCs remain to be clarified. RESEARCH DESIGN AND METHODS We investigated the molecular mechanisms underlying the immunosuppressive effects of MSCs in vitro and in vivo. RESULTS Our results demonstrate that matrix metalloproteinases (MMPs) secreted by MSCs, in particular MMP-2 and MMP-9, play an important role in the suppressive activity of MSCs by reducing surface expression of CD25 on responding T-cells. Blocking the activity of MMP-2 and MMP-9 in vitro completely abolished the suppression of T-cell proliferation by MSCs and restored T-cell expression of CD25 as well as responsiveness to interleukin-2. In vivo, administration of MSCs significantly reduced delayed-type hypersensitivity responses to allogeneic antigen and profoundly prolonged the survival of fully allogeneic islet grafts in transplant recipients. Significantly, these MSC-mediated protective effects were completely reversed by in vivo inhibition of MMP-2 and MMP-9. CONCLUSIONS We demonstrate that MSCs can prevent islet allograft rejection leading to stable, long-term normoglycemia. In addition, we provide a novel insight into the mechanism underlying the suppressive effects of MSCs on T-cell responses to alloantigen. Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. See accompanying commentary, p. 1728 . Received March 3, 2009. Accepted May 6, 2009. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. © 2009 by the American Diabetes Association.

The Tasmanian devil, a large carnivorous Australian marsupial, is under threat from a widespread fatal disease in which a malignant oral-facial tumour obstructs the animal's ability to feed. Here we show that the chromosomes in these tumours have undergone a complex rearrangement that is identical for every animal studied. In light of this remarkable finding and of the known fighting behaviour of the devils, we propose that the disease is transmitted by allograft, whereby an infectious cell line is passed directly between the animals through bites they inflict on one another.

Alloreactive memory T cells may be refractory to many of the tolerance-inducing strategies that are effective against naive T cells and thus present a significant barrier to long-term allograft survival. Because CD4⁺CD25⁺ regulatory T cells (Tregs) are critical elements of many approaches to successful induction/maintenance of transplantation tolerance, we used MHC class I and II alloreactive TCR-transgenic models to explore the ability of antigen-specific Tregs to control antigen-specific memory T cell responses. Upon coadoptive transfer into RAG-1⁻/⁻ mice, we found that Tregs effectively suppressed the ability of naive T cells to reject skin grafts, but neither antigen-unprimed nor antigen-primed Tregs suppressed rejection by memory T cells. Interestingly, different mechanisms appeared to be active in the ability of Tregs to control naive T cell-mediated graft rejection in the class II versus class I alloreactive models. In the former case, we observed decreased early expansion of effector cells in lymphoid tissue. In contrast, in the class I model, an effect of Tregs on early proliferation and expansion was not observed. However, at a late time point, significant differences in cell numbers were seen, suggesting effects on responding T cell survival. Overall, these data indicate that the relative resistance of both CD4⁺ and CD8⁺ alloreactive memory T cells to regulation may mediate resistance to tolerance induction seen in hosts with preexisting alloantigen-specific immunity and further indicate the multiplicity of mechanisms by which Tregs may control alloimmune responses in vivo.