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• W2019946509 abstract "Although it is commonly accepted that allogeneic hematopoietic cell transplant (HCT) recipients develop transplantation tolerance and can quickly discontinue all immunosuppressive drugs, existing data does not support this concept. Most patients will require a prolonged duration of immunosuppression, lasting commonly several years. This has even greater importance, as the majority of transplants are now performed utilizing peripheral blood mobilized stem cells, which are associated with an increased risk of chronic graft-versus-host disease (cGVHD) and prolonged duration of immunosuppression. Despite these challenges, the approach to liberation from immunosuppression after HCT is empiric, and biomarkers of operational tolerance after HCT are lacking. Conversely, investigators in solid organ allografting have begun to examine tolerance associated gene expression in renal and hepatic allograft recipients. Significant challenges in the design and interpretation of these studies potentially limit comparisons. However, a relatively unified model is beginning to emerge, which largely recapitulates previously established mechanisms of immune tolerance. This evidence supports a state of immune quiescence with reduced expression of costimulation and immune response genes, and upregulation of cell cycle control genes. Data indirectly supports the importance of tumor growth factor (TGF)-β, supports the role of CD4+CD25+ regulatory T cells, and offers new insights into the role of natural killer (NK) cells. Distinct in hepatic allograft tolerance, emerging evidence highlights the importance of γδT cells, and selection of the Vγδ1+ subtype among the γδT cell population. The deficiencies in the current understanding of transplantation tolerance after HCT, as well as the inadequacies evident in the current empiric approach to immunosuppressive medication (IS) management after HCT make clear the rationale for investigation aimed at elucidating tolerance associated biomarkers after HCT. Although it is commonly accepted that allogeneic hematopoietic cell transplant (HCT) recipients develop transplantation tolerance and can quickly discontinue all immunosuppressive drugs, existing data does not support this concept. Most patients will require a prolonged duration of immunosuppression, lasting commonly several years. This has even greater importance, as the majority of transplants are now performed utilizing peripheral blood mobilized stem cells, which are associated with an increased risk of chronic graft-versus-host disease (cGVHD) and prolonged duration of immunosuppression. Despite these challenges, the approach to liberation from immunosuppression after HCT is empiric, and biomarkers of operational tolerance after HCT are lacking. Conversely, investigators in solid organ allografting have begun to examine tolerance associated gene expression in renal and hepatic allograft recipients. Significant challenges in the design and interpretation of these studies potentially limit comparisons. However, a relatively unified model is beginning to emerge, which largely recapitulates previously established mechanisms of immune tolerance. This evidence supports a state of immune quiescence with reduced expression of costimulation and immune response genes, and upregulation of cell cycle control genes. Data indirectly supports the importance of tumor growth factor (TGF)-β, supports the role of CD4+CD25+ regulatory T cells, and offers new insights into the role of natural killer (NK) cells. Distinct in hepatic allograft tolerance, emerging evidence highlights the importance of γδT cells, and selection of the Vγδ1+ subtype among the γδT cell population. The deficiencies in the current understanding of transplantation tolerance after HCT, as well as the inadequacies evident in the current empiric approach to immunosuppressive medication (IS) management after HCT make clear the rationale for investigation aimed at elucidating tolerance associated biomarkers after HCT. IntroductionIn the field of transplantation, a major unsolved problem is immunologic tolerance. Immunosuppressive medications (IS) allow the transplantation of allografts without life-threatening overactivated immune response, but several issues remain. In solid organ transplantation, most recipients will require life-long IS and suffer the morbidity of this therapy, yet, they still are at risk for acute and chronic graft rejection. In allogeneic hematopoietic cell transplantation (HCT), immunosuppression is necessary to prevent graft rejection and also to temper an immunologic reaction of donor immune cells against the host. This reaction, namely, graft-versus-host disease (GVHD), is the major source of treatment-related morbidity and mortality (TRM). Importantly, efforts at liberation from IS are empiric, as clinicians are unable to discern drug-suppressed immune response from the development of tolerance. A state of operational tolerance, defined as stable graft function and absence of ongoing immunologic injury because of incompatibility between donor and recipient in the absence of ongoing IS therapy, is infrequently reached in solid organ allografting. Novel investigation utilizing gene expression profiling after solid organ transplantation has begun to identify biomarkers of tolerance that may ultimately allow for rational trials of immunosuppression liberation. Although there are several challenges in the conduct and interpretation of this work, a preliminary profile of immunoregulatory cells and differential gene expression is beginning to emerge. Much of the findings recapitulate previous experimentally established mechanisms integral to immunologic tolerance. We begin here by reviewing mechanisms of immunologic tolerance, and then provide a conceptual framework for microarray analysis of gene expression. Next, we review the literature on tolerance-associated gene expression and immunophenotyping to date in renal and hepatic transplant. Challenges in the design and analysis of this work are then discussed. A provisional unifying model of tolerance-associated gene expression is presented. Finally, we conclude with a discussion of future directions of this work with attention to its application to allogeneic HCT.Immunologic ToleranceImmunologic tolerance is a complex process that, in the case of transplantation of allogeneic hematopoietic stem cells (HSCs) or solid organs, is clinically characterized by stable graft function and absence of ongoing immunologic injury because of incompatibility between donor and recipient—as manifested by GVHD in allogeneic HCT or graft rejection in solid organ transplantation—in the absence of ongoing IS therapy [1Zarkhin V. Sarwal M.M. Microarrays: monitoring for transplant tolerance and mechanistic insights.Clin Lab Med. 2008; 28 (vi): 385-410Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, 2Goodnow C.C. Sprent J. Fazekas de St Groth B. Vinuesa C.G. Cellular and genetic mechanisms of self tolerance and autoimmunity.Nature. 2005; 435: 590-597Crossref PubMed Scopus (529) Google Scholar, 3Kingsley C.I. Nadig S.N. Wood K.J. Transplantation tolerance: lessons from experimental rodent models.Transpl Int. 2007; 20: 828-841Crossref PubMed Scopus (53) Google Scholar]. Investigation into the molecular mechanisms responsible for immunologic tolerance has implicated several active processes [4Van Parijs L. Abbas A.K. Homeostasis and self-tolerance in the immune system: turning lymphocytes off.Science. 1998; 280: 243-248Crossref PubMed Scopus (832) Google Scholar, 5Suthanthiran M. Transplantation tolerance: fooling mother nature.Proc Natl Acad Sci USA. 1996; 93: 12072-12075Crossref PubMed Scopus (22) Google Scholar, 6Salama A.D. Remuzzi G. Harmon W.E. Sayegh M.H. Challenges to achieving clinical transplantation tolerance.J Clin Invest. 2001; 108: 943-948Crossref PubMed Scopus (114) Google Scholar, 7Li X.C. Strom T.B. Turka L.A. Wells A.D. T cell death and transplantation tolerance.Immunity. 2001; 14: 407-416Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar]. Through central deletion, developing T cells with high affinity T cell receptors (TCRs) for major histocompatibility complex (MHC)/antigen complex presented by thymic antigen presenting cells (APCs) undergo apoptosis [8Kurtz J. Shaffer J. Lie A. Anosova N. Benichou G. Sykes M. Mechanisms of early peripheral CD4 T-cell tolerance induction by anti-CD154 monoclonal antibody and allogeneic bone marrow transplantation: evidence for anergy and deletion but not regulatory cells.Blood. 2004; 103: 4336-4343Crossref PubMed Scopus (98) Google Scholar]. As HCT facilitates central tolerance, the major problem after HCT is failure to achieve peripheral tolerance. Mature T cells may undergo peripheral deletion after presentation of self-antigen by dendritic cells (DCs) under noninflammatory conditions, with exhaustion after antigenic stimulus, or through the suppression by regulatory cells [9Zhang Z.X. Yang L. Young K.J. DuTemple B. Zhang L. Identification of a previously unknown antigen-specific regulatory T cell and its mechanism of suppression.Nat Med. 2000; 6: 782-789Crossref PubMed Scopus (369) Google Scholar, 10Sykes M. Immune tolerance: mechanisms and application in clinical transplantation.J Intern Med. 2007; 262: 288-310Crossref PubMed Scopus (59) Google Scholar, 11Heath W.R. Kurts C. Miller J.F. Carbone F.R. Cross-tolerance: a pathway for inducing tolerance to peripheral tissue antigens.J Exp Med. 1998; 187: 1549-1553Crossref PubMed Scopus (193) Google Scholar, 12Ferber I. Schonrich G. Schenkel J. Mellor A.L. Hammerling G.J. Arnold B. Levels of peripheral T cell tolerance induced by different doses of tolerogen.Science. 1994; 263: 674-676Crossref PubMed Scopus (208) Google Scholar]. T cells may also become anergic through mechanisms including incomplete costimulatory molecule signaling [13Wekerle T. Kurtz J. Ito H. et al.Allogeneic bone marrow transplantation with co-stimulatory blockade induces macrochimerism and tolerance without cytoreductive host treatment.Nat Med. 2000; 6: 464-469Crossref PubMed Scopus (449) Google Scholar, 14Schwartz R.H. Costimulation of T lymphocytes: the role of CD28, CTLA-4, and B7/BB1 in interleukin-2 production and immunotherapy.Cell. 1992; 71: 1065-1068Abstract Full Text PDF PubMed Scopus (1229) Google Scholar, 15Larsen C.P. Elwood E.T. Alexander D.Z. et al.Long-term acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathways.Nature. 1996; 381: 434-438Crossref PubMed Scopus (1274) Google Scholar, 16Guinan E.C. Boussiotis V.A. Neuberg D. et al.Transplantation of anergic histoincompatible bone marrow allografts.N Engl J Med. 1999; 340: 1704-1714Crossref PubMed Scopus (372) Google Scholar, 17Durham M.M. Bingaman A.W. Adams A.B. et al.Cutting edge: administration of anti-CD40 ligand and donor bone marrow leads to hemopoietic chimerism and donor-specific tolerance without cytoreductive conditioning.J Immunol. 2000; 165: 1-4PubMed Google Scholar, 18Adams A.B. Durham M.M. Kean L. et al.Costimulation blockade, busulfan, and bone marrow promote titratable macrochimerism, induce transplantation tolerance, and correct genetic hemoglobinopathies with minimal myelosuppression.J Immunol. 2001; 167: 1103-1111PubMed Google Scholar], exposure to low-affinity antigenic ligands, through cytokines elaborated by tolerogenic DC [19Thomson A.W. Lu L. Dendritic cells as regulators of immune reactivity: implications for transplantation.Transplantation. 1999; 68: 1-8Crossref PubMed Scopus (99) Google Scholar, 20Lechler R. Ng W.F. Steinman R.M. Dendritic cells in transplantation—friend or foe?.Immunity. 2001; 14: 357-368Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar], and through suppressive effects of regulatory T cells [21Merrell K.T. Benschop R.J. Gauld S.B. et al.Identification of anergic B cells within a wild-type repertoire.Immunity. 2006; 25: 953-962Abstract Full Text Full Text PDF PubMed Scopus (220) Google Scholar, 22Macian F. Im S.H. Garcia-Cozar F.J. Rao A. T-cell anergy.Curr Opin Immunol. 2004; 16: 209-216Crossref PubMed Scopus (122) Google Scholar, 23Lechler R. Chai J.G. Marelli-Berg F. Lombardi G. The contributions of T-cell anergy to peripheral T-cell tolerance.Immunology. 2001; 103: 262-269Crossref PubMed Scopus (82) Google Scholar, 24Vanasek T.L. Nandiwada S.L. Jenkins M.K. Mueller D.L. CD25 + Foxp3+ regulatory T cells facilitate CD4 + T cell clonal anergy induction during the recovery from lymphopenia.J Immunol. 2006; 176: 5880-5889PubMed Google Scholar, 25Rutella S. Danese S. Leone G. Tolerogenic dendritic cells: cytokine modulation comes of age.Blood. 2006; 108: 1435-1440Crossref PubMed Scopus (426) Google Scholar, 26Appleman L.J. Boussiotis V.A. T cell anergy and costimulation.Immunol Rev. 2003; 192: 161-180Crossref PubMed Scopus (236) Google Scholar]. Tolerance has also been experimentally established by the induction of mixed host-donor chimerism [27Sykes M. Sachs D.H. Mixed allogeneic chimerism as an approach to transplantation tolerance.Immunol Today. 1988; 9: 23-27Abstract Full Text PDF PubMed Scopus (151) Google Scholar, 28Sharabi Y. Sachs D.H. Mixed chimerism and permanent specific transplantation tolerance induced by a nonlethal preparative regimen.J Exp Med. 1989; 169: 493-502Crossref PubMed Scopus (572) Google Scholar, 29Myburgh J.A. Smit J.A. Stark J.H. Browde S. Total lymphoid irradiation in kidney and liver transplantation in the baboon: prolonged graft survival and alterations in T cell subsets with low cumulative dose regimens.J Immunol. 1984; 132: 1019-1025PubMed Google Scholar, 30Ildstad S.T. Sachs D.H. Reconstitution with syngeneic plus allogeneic or xenogeneic bone marrow leads to specific acceptance of allografts or xenografts.Nature. 1984; 307: 168-170Crossref PubMed Scopus (687) Google Scholar, 31Gianello P.R. Fishbein J.M. Rosengard B.R. et al.Tolerance to class I-disparate renal allografts in miniature swine. Maintenance of tolerance despite induction of specific antidonor CTL responses.Transplantation. 1995; 59: 772-777Crossref PubMed Scopus (36) Google Scholar, 32Cobbold S.P. Adams E. Marshall S.E. Davies J.D. Waldmann H. Mechanisms of peripheral tolerance and suppression induced by monoclonal antibodies to CD4 and CD8.Immunol Rev. 1996; 149: 5-33Crossref PubMed Google Scholar]. As well, both naturally occurring and inducible CD4+CD25+FoxP3+ regulatory T cells have been shown to be important mediators of immune tolerance; their suppressive effect is thought to be mediated through cell contact, as well as mediated by tumor growth factor (TGF)-β, leading to suppression of alloreactive T cells. TGF-β has also been shown to have important effects on DC, leading to their tolerogenic effect on T cells [25Rutella S. Danese S. Leone G. Tolerogenic dendritic cells: cytokine modulation comes of age.Blood. 2006; 108: 1435-1440Crossref PubMed Scopus (426) Google Scholar, 33Trani J. Moore D.J. Jarrett B.P. et al.CD25+ immunoregulatory CD4 T cells mediate acquired central transplantation tolerance.J Immunol. 2003; 170: 279-286PubMed Google Scholar, 34Oluwole S.F. Oluwole O.O. DePaz H.A. Adeyeri A.O. Witkowski P. Hardy M.A. CD4 + CD25+ regulatory T cells mediate acquired transplant tolerance.Transpl Immunol. 2003; 11: 287-293Crossref PubMed Scopus (28) Google Scholar, 35Nguyen V.H. Zeiser R. Negrin R.S. Role of naturally arising regulatory T cells in hematopoietic cell transplantation.Biol Blood Marrow Transplant. 2006; 12: 995-1009Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar, 36Le N.T. Chao N. Regulating regulatory T cells.Bone Marrow Transplant. 2007; 39: 1-9Crossref PubMed Scopus (46) Google Scholar, 37Hoffmann P. Ermann J. Edinger M. Fathman C.G. Strober S. Donor-type CD4(+)CD25(+) regulatory T cells suppress lethal acute graft-versus-host disease after allogeneic bone marrow transplantation.J Exp Med. 2002; 196: 389-399Crossref PubMed Scopus (907) Google Scholar, 38Takahashi T. Tagami T. Yamazaki S. et al.Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4.J Exp Med. 2000; 192: 303-310Crossref PubMed Scopus (1797) Google Scholar, 39Sakaguchi S. Sakaguchi N. Asano M. Itoh M. Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases.J Immunol. 1995; 155: 1151-1164PubMed Google Scholar]. B cell deletion and anergy [40Kawahara T. Shimizu I. Ohdan H. Zhao G. Sykes M. Differing mechanisms of early and late B cell hyporesponsiveness induced by mixed chimerism.Am J Transplant. 2005; 5: 2821-2829Crossref PubMed Scopus (28) Google Scholar, 41Ferry H. Leung J.C. Lewis G. et al.B-cell tolerance.Transplantation. 2006; 81: 308-315Crossref PubMed Scopus (19) Google Scholar] are not thought to be relevant mechanisms of immune tolerance after HCT. Finally, emerging work has shed new light on the importance of the innate immune system, including natural killer (NK) cells, which have been shown to be important mediators of transplantation tolerance through effects on antigen presenting cells and alloreactive T cells [42LaRosa D.F. Rahman A.H. Turka L.A. The innate immune system in allograft rejection and tolerance.J Immunol. 2007; 178: 7503-7509PubMed Google Scholar, 43Yu G. Xu X. Vu M.D. Kilpatrick E.D. Li X.C. NK cells promote transplant tolerance by killing donor antigen-presenting cells.J Exp Med. 2006; 203: 1851-1858Crossref PubMed Scopus (236) Google Scholar, 44Goldstein D.R. Thomas J.M. Kirklin J.K. George J.F. An essential role for natural killer cells in augmentation of allograft survival mediated by donor spleen cells.Transplantation. 2001; 72: 954-956Crossref PubMed Scopus (9) Google Scholar, 45Beilke J.N. Kuhl N.R. Van Kaer L. Gill R.G. NK cells promote islet allograft tolerance via a perforin-dependent mechanism.Nat Med. 2005; 11: 1059-1065Crossref PubMed Scopus (164) Google Scholar]. In total, experimental evidence to date demonstrates a diversity of mechanisms underlying immune tolerance.Microarray AnalysisMicroarray technology provides an opportunity to simultaneously analyze the expression of thousands of genes. Investigations using this technology have provided an improved understanding of the molecular mechanisms of disease, characterization of disease classes, prognostic classification, and the development of biomarkers for response to treatment. The power of microarray technology is not just in the thousands of genes that are measured in a single assay, but also in the ability to archive the data and use it again to address different biological questions.Structurally, the microarray platform consists of DNA, either synthesized oligonucleotides or purified cDNA molecules, affixed to a structural support. These probes are used to capture labeled target molecules from an experimental sample. By quantifying the amount captured, a measure is made of each individual RNA species in a complex mixture from cells or tissues [1Zarkhin V. Sarwal M.M. Microarrays: monitoring for transplant tolerance and mechanistic insights.Clin Lab Med. 2008; 28 (vi): 385-410Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, 46Shah S. Sarwal M.M. Microarrays: interrogating the transplant transcriptosome.Clin Transpl. 2004; : 261-267PubMed Google Scholar, 47Sarwal M.M. Li L. Designer genes: filling the gap in transplantation.Transplantation. 2006; 82: 1261-1272Crossref PubMed Scopus (12) Google Scholar, 48Chua M.S. Sarwal M.M. Microarrays: new tools for transplantation research.Pediatr Nephrol. 2003; 18: 319-327PubMed Google Scholar, 49Butte A. The use and analysis of microarray data.Nat Rev. 2002; 1: 951-960Google Scholar, 50Boussioutas A. Haviv I. Current and potential uses for DNA microarrays in transplantation medicine: lessons from other disciplines.Tissue Antigens. 2003; 62: 93-103Crossref PubMed Scopus (2) Google Scholar]. The data is further evaluated for quality to remove questionable data, normalized to account for array-to-array intensity bias, and filtered to remove background signal noise.As in standard biological experimentation, the key factors in successful microarray analysis are solid experimental design and the correct selection of biological samples, ensuring that the output of the analysis is related to the biological question at hand. Several methods are available for the actual analysis of microarray data [48Chua M.S. Sarwal M.M. Microarrays: new tools for transplantation research.Pediatr Nephrol. 2003; 18: 319-327PubMed Google Scholar, 51Golub T.R. Slonim D.K. Tamayo P. et al.Molecular classification of cancer: class discovery and class prediction by gene expression monitoring.Science. 1999; 286: 531-537Crossref PubMed Scopus (9129) Google Scholar, 52Alizadeh A.A. Eisen M.B. Davis R.E. et al.Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling.Nature. 2000; 403: 503-511Crossref PubMed Scopus (7914) Google Scholar]. The initial step is usually a statistical filtering for genes that are differentially expressed between samples of 2 different classes, such as control versus experimental. The analysis might use a standard Student's t-test or statistical analysis of microarrays (SAM) [53Tusher V.G. Tibshirani R. Chu G. Significance analysis of microarrays applied to the ionizing radiation response.Proc Natl Acad Sci USA. 2001; 98: 5116-5121Crossref PubMed Scopus (9704) Google Scholar]. This technique uses a modified t-test coupled with a permutation analysis to control for false discoveries. However, many other statistical methods have been used. In direct class comparisons, the end result is normally a list of the potential gene expression differences between the 2 classes. Additionally, methods exist for comparing multiple classes to each other. This analysis often involves a clustering or classification algorithm such as prediction analysis of microarrays (PAM) [54Tibshirani R. Hastie T. Narasimhan B. Chu G. Diagnosis of multiple cancer types by shrunken centroids of gene expression.Proc Natl Acad Sci USA. 2002; 99: 6567-6572Crossref PubMed Scopus (2137) Google Scholar]. The goal of clustering is to define classes or biological groups containing each experimental sample and to delineate how closely each of the groups is related.Microarray experiments generally involve far more genes than samples, and care must therefore be taken to address and/or correct for false discovery caused by multiple testing. Interpreting the results in the context of the biologic system in question can assist in selection of relevant genes during this step.In some cases, a classifier is constructed to separate new samples into biologically relevant classes. The accepted practice in classifier construction is to use a training set of data for which the phenotype of interest is known for each sample. The gene expression values are used to teach the classifier to categorize the samples according to their class phenotype. Proof of the correctness of the developed classification scheme is then realized with a test set of data. Good classification accuracy on an independent group of samples is the best assurance of the quality of the classifier. Although many components of microarray analysis are still the focus of active investigation, this powerful tool makes possible an enhanced understanding of the molecular underpinnings of biological processes. This technology has been utilized to better understand the nature of transplantation related immune tolerance.Microarray Analysis of Solid-Organ Transplantation in the Clinical SettingSeveral studies have utilized microarray technology to investigate transplantation tolerance. The ultimate goal of such work is to define a gene expression and cellular composition profile in allograft recipients that would indicate whether or not it is possible to liberate these patients from IS safely. These studies have compared gene expression between operationally tolerant individuals, variably defined nontolerant comparators (chronic rejection versus those that have attempted and failed IS taper), and healthy control subjects. The design of these studies, which have been driven by pragmatic concerns given the rarity of tolerant solid organ allograft recipients, makes it difficult to discern whether the differential gene expression reported is because of immunosuppressive drugs (ie, on IS versus off IS), immunologic resting versus active state (ie, normal versus rejection), or a tolerant versus nontolerant state; although the denominator, or total number of subjects from which these subjects were selected, is not provided in these studies, the tolerant clinical phenotype is reported to be <5% in renal allografts and <20% in hepatic allografts. Although these are significant challenges to the interpretation of this work, similarities in the results emerge that reinforce concepts developed by prior laboratory experimentation.Brouard et al. [55Brouard S. Mansfield E. Braud C. et al.Identification of a peripheral blood transcriptional biomarker panel associated with operational renal allograft tolerance.Proc Natl Acad Sci USA. 2007; 104: 15448-15453Crossref PubMed Scopus (297) Google Scholar] studied differential gene expression in peripheral blood mononuclear cells (PBMC) on a lymphochip platform comprised of 11,820 genes with the aim of discerning biomarkers for operational tolerance in renal transplant recipients. The study sample was divided into a training and test set. The training group consisted of 5 tolerant (TOL) subjects (defined as IS free for at least 2 years with stable graft function), 11 chronic rejection (CR) subjects (defined by clinical and biopsy-proven chronic rejection), and 8 healthy control (N) subjects. The investigators identified a 49 gene signature by PAM, and then applied this classifier to the test set, where the sensitivity and specificity were 90% and 100%, respectively. Validation was also performed with reverse transcriptase-polymerase chain reaction (RT-PCR). The investigators also examined the prevalence of this 49 gene signature in MIS (defined as those on steroid monotherapy) and STA (stable on long-term IS) subjects; 50% of the MIS subjects and 1 of 12 STA subjects fit this phenotype. Although this finding may provide rationale for IS liberation in this large proportion of cases on steroid monotherapy, this could only be conclusively determined in a prospective trial of IS liberation.Several important insights emerge from this work: first, the investigators confirm previous experimental literature, demonstrating significantly increased expression of FOXP3, as well as increased expression of neuropilin-1 and GITR in the TOL group [56Shimizu J. Yamazaki S. Sakaguchi S. Induction of tumor immunity by removing CD25 + CD4 + T cells: a common basis between tumor immunity and autoimmunity.J Immunol. 1999; 163: 5211-5218PubMed Google Scholar, 57Cobbold S.P. Castejon R. Adams E. et al.Induction of foxP3+ regulatory T cells in the periphery of T cell receptor transgenic mice tolerized to transplants.J Immunol. 2004; 172: 6003-6010PubMed Google Scholar, 58Bruder D. Probst-Kepper M. Westendorf A.M. et al.Neuropilin-1: a surface marker of regulatory T cells.Eur J Immunol. 2004; 34: 623-630Crossref PubMed Scopus (384) Google Scholar]. Second, they identified 3 distinct gene clusters that separated the TOL from CR subjects, including reduced immune activation, downregulation of signal transduction genes and RNA binding genes, as well as upregulated cell cycle regulator genes [55Brouard S. Mansfield E. Braud C. et al.Identification of a peripheral blood transcriptional biomarker panel associated with operational renal allograft tolerance.Proc Natl Acad Sci USA. 2007; 104: 15448-15453Crossref PubMed Scopus (297) Google Scholar, 59Saed G.M. Kruger M. Diamond M.P. Expression of transforming growth factor-beta and extracellular matrix by human peritoneal mesothelial cells and by fibroblasts from normal peritoneum and adhesions: effect of Tisseel.Wound Repair Regen. 2004; 12: 557-564Crossref PubMed Scopus (36) Google Scholar, 60Bellone G. Aste-Amezaga M. Trinchieri G. Rodeck U. Regulation of NK cell functions by TGF-beta 1.J Immunol. 1995; 155: 1066-1073PubMed Google Scholar]. Next, prior evidence of the importance of TGF-β in immune tolerance is corroborated; although the absolute serum levels of TGF-β did not differ across groups, 27% of the differentially expressed genes in TOL versus CR are regulated by TGF-β [61Verrecchia F. Tacheau C. Wagner E.F. Mauviel A. A central role for the JNK pathway in mediating the antagonistic activity of pro-inflammatory cytokines against transforming growth factor-beta-driven SMAD3/4-specific gene expression.J Biol Chem. 2003; 278: 1585-1593Crossref PubMed Scopus (81) Google Scholar, 62Satterwhite D.J. Neufeld K.L. TGF-beta targets the Wnt pathway components, APC and beta-catenin, as Mv1Lu cells undergo cell cycle arrest.Cell Cycle. 2004; 3: 1069-1073Crossref PubMed Google Scholar, 63Hattori T. Kawaki H. Kubota S. et al.Downregulation of a rheumatoid arthritis-related antigen (RA-A47) by ra-a47 antisense oligonucleotides induces inflammatory factors in chondrocytes.J Cell Physiol. 2003; 197: 94-102Crossref PubMed Scopus (14) Google Scholar]. Also, in support of major established mechanisms of immune tolerance, the authors demonstrated reduced expression of genes relevant to T cell costimulation, T cell activation, cytotoxicity effectors, and pro-inflammatory cytokines. In total, these findings support a state of immune quiescence, and recapitulate several previously established mechanisms of immune tolerance [55Brouard S. Mansfield E. Braud C. et al.Identification of a peripheral blood transcriptional biomarker panel associated with operational r" @default.
• W2019946509 created "2016-06-24" @default.
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• W2019946509 date "2010-06-01" @default.
• W2019946509 modified "2023-09-23" @default.
• W2019946509 title "Biomarkers to Discern Transplantation Tolerance after Allogeneic Hematopoietic Cell Transplantation" @default.
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