1 5147 129 POTENTIAL ROLES OF LONG NONCODING RNAS AS THERAPEUTIC TARGETS IN ORGAN TRANSPLANTATION. ORGAN TRANSPLANTATION IS THE MOST PREFERRED TREATMENT OPTION FOR END-STAGE ORGAN DISEASES; HOWEVER, ALLOGRAFT REJECTION IS THE MAJOR HURDLE IN SUCCESSFUL LONG-TERM TRANSPLANT SURVIVAL. IN SPITE OF DEVELOPING BETTER HLA MATCHING AND MORE EFFECTIVE IMMUNOSUPPRESSIVE REGIMEN, ONE-YEAR GRAFT SURVIVAL HAS BEEN INCREASED BY NEARLY 90% AND THE INCIDENCE OF ACUTE REJECTION BY ONE-YEAR POST-TRANSPLANTATION HAS BEEN DECREASED BY 12.2% IN THE LAST DECADES, CHRONIC ALLOGRAFT REJECTION HAS REMAINED AS ONE OF THE MAJOR OBSTACLES TO THE LONG-LASTING SURVIVAL OF THE TRANSPLANTED ALLOGRAFT. THEREFORE, SEEMINGLY PREVENTING THE ALLOGRAFT REJECTION AND INDUCING IMMUNOLOGICAL TOLERANCE AGAINST TRANSPLANTED ALLOGRAFTS IS ONE OF THE PRIMARY GOALS IN TRANSPLANTATION RESEARCH TO ENABLE LONG-LASTING GRAFT SURVIVAL. VARIOUS MECHANISMS SUCH AS LONG NONCODING RNAS (LNCRNAS) HAVE BEEN PROPOSED THAT INDUCE IMMUNE TOLERANCE BY MODULATING THE GENE EXPRESSION AND REGULATING INNATE AND ADAPTIVE IMMUNE RESPONSES DURING TRANSPLANTATION. BESIDES, BECAUSE OF INVOLVEMENT IN REGULATING EPIGENETIC, TRANSCRIPTIONAL, AND POST-TRANSLATIONAL MECHANISMS, LNCRNAS COULD AFFECT ALLOGRAFT STATUS. THEREFORE, THESE MOLECULES COULD BE CONSIDERED AS THE POTENTIAL TARGETS FOR PREDICTION, PROGNOSIS, DIAGNOSIS, AND TREATMENT OF GRAFT REJECTION. IT IS SUGGESTED THAT THE NONINVASIVE PREDICTIVE BIOMARKERS HOLD PROMISE TO OVERCOME THE CURRENT LIMITATIONS OF CONVENTIONAL TISSUE BIOPSY IN THE DIAGNOSIS OF REJECTION. HENCE, THIS REVIEW AIMS TO PROVIDE A COMPREHENSIVE OVERVIEW OF LNCRNAS AND THEIR FUNCTION TO FACILITATE DIAGNOSIS, PROGNOSIS, AND PREDICTION OF THE RISK OF GRAFT REJECTION, AND THE SUGGESTIVE THERAPEUTIC CHOICES AFTER TRANSPLANTATION. 2022 2 3861 30 ISOLATION OF HUMAN ANTIGEN-SPECIFIC REGULATORY T CELLS WITH HIGH SUPPRESSIVE FUNCTION. ADOPTIVE TRANSFER OF REGULATORY T (TREG) CELLS COULD BE AN ALTERNATIVE TO CHRONIC IMMUNOSUPPRESSION FOR PREVENTION OF ALLOGENEIC GRAFT REJECTION. WHILE POLYSPECIFIC TREG CELLS CAN PREVENT IMMUNE RESPONSES UNDER LYMPHOPENIC CONDITIONS, AG-SPECIFIC TREG CELLS ARE NEEDED TO TREAT AUTOIMMUNITY AND GRAFT REJECTION. YET, RELIABLE MARKERS FOR AG-SPECIFIC TREG CELLS ARE MISSING. WE REPORT THAT LATENCY-ASSOCIATED PEPTIDE (LAP) AND GLYCOPROTEIN A REPETITIONS PREDOMINANT (GARP) CAN IDENTIFY HUMAN AG-SPECIFIC TREG CELLS. IN ADDITION, WE SHOW THAT THE DEPLETION OF CD154(+) CELLS FROM LAP(+) OR GARP(+) TREG CELLS INCREASES THE TREG-CELL PURITY TO OVER 90%, AS ASSESSED BY EPIGENETIC ANALYSIS. THESE AG-SPECIFIC TREG CELLS CAN BE ISOLATED MAGNETICALLY AND MIGHT CONTRIBUTE TO THE DEVELOPMENT OF GMP-BASED PROTOCOLS. IN ADDITION, AG-SPECIFIC TREG CELLS ARE FUNCTIONALLY FAR SUPERIOR TO CD4(+) CD25(HIGH) OR CD4(+) CD25(HIGH) CD127(LOW) TREG CELLS IN VITRO AND IN PREVENTING STRONG ALLOREACTIONS IN HUMANIZED MICE. THEY COULD, THEREFORE, HAVE A HIGH THERAPEUTIC POTENTIAL FOR THE CONTROL OF ALLOIMMUNE, AUTOIMMUNE, AND ALLERGIC IMMUNE RESPONSES IN PATIENTS. 2014 3 4058 24 MARKERS OF REJECTION OF A LUNG ALLOGRAFT: STATE OF THE ART. CHRONIC LUNG ALLOGRAFT DYSFUNCTION (CLAD) AFFECTS APPROXIMATELY 50% OF ALL LUNG TRANSPLANT RECIPIENTS BY 5 POST-OPERATIVE YEARS AND IS THE LEADING CAUSE OF DEATH IN LUNG TRANSPLANT RECIPIENTS. EARLY CLAD DIAGNOSIS OR IDEALLY PREDICTION OF CLAD IS ESSENTIAL TO ENABLE EARLY INTERVENTION BEFORE SIGNIFICANT LUNG INJURY OCCURS. NEW TECHNOLOGIES HAVE EMERGED TO FACILITATE BIOMARKER DISCOVERY, INCLUDING EPIGENETIC MODIFICATION AND SINGLE-CELL RNA SEQUENCING. THIS REVIEW EXAMINES NEW AND EXISTING TECHNOLOGIES FOR BIOMARKER DISCOVERY AND THE CURRENT STATE OF RESEARCH ON BIOMARKERS FOR IDENTIFYING LUNG TRANSPLANT REJECTION. 2022 4 3716 31 INHIBITING INFLAMMATION WITH MYELOID CELL-SPECIFIC NANOBIOLOGICS PROMOTES ORGAN TRANSPLANT ACCEPTANCE. INDUCING GRAFT ACCEPTANCE WITHOUT CHRONIC IMMUNOSUPPRESSION REMAINS AN ELUSIVE GOAL IN ORGAN TRANSPLANTATION. USING AN EXPERIMENTAL TRANSPLANTATION MOUSE MODEL, WE DEMONSTRATE THAT LOCAL MACROPHAGE ACTIVATION THROUGH DECTIN-1 AND TOLL-LIKE RECEPTOR 4 (TLR4) DRIVES TRAINED IMMUNITY-ASSOCIATED CYTOKINE PRODUCTION DURING ALLOGRAFT REJECTION. WE CONDUCTED NANOIMMUNOTHERAPEUTIC STUDIES AND FOUND THAT A SHORT-TERM MTOR-SPECIFIC HIGH-DENSITY LIPOPROTEIN (HDL) NANOBIOLOGIC TREATMENT (MTORI-HDL) AVERTED MACROPHAGE AEROBIC GLYCOLYSIS AND THE EPIGENETIC MODIFICATIONS UNDERLYING INFLAMMATORY CYTOKINE PRODUCTION. THE RESULTING REGULATORY MACROPHAGES PREVENTED ALLOREACTIVE CD8(+) T CELL-MEDIATED IMMUNITY AND PROMOTED TOLEROGENIC CD4(+) REGULATORY T (TREG) CELL EXPANSION. TO ENHANCE THERAPEUTIC EFFICACY, WE COMPLEMENTED THE MTORI-HDL TREATMENT WITH A CD40-TRAF6-SPECIFIC NANOBIOLOGIC (TRAF6I-HDL) THAT INHIBITS CO-STIMULATION. THIS SYNERGISTIC NANOIMMUNOTHERAPY RESULTED IN INDEFINITE ALLOGRAFT SURVIVAL. TOGETHER, WE SHOW THAT HDL-BASED NANOIMMUNOTHERAPY CAN BE EMPLOYED TO CONTROL MACROPHAGE FUNCTION IN VIVO. OUR STRATEGY, FOCUSED ON PREVENTING INFLAMMATORY INNATE IMMUNE RESPONSES, PROVIDES A FRAMEWORK FOR DEVELOPING TARGETED THERAPIES THAT PROMOTE IMMUNOLOGICAL TOLERANCE. 2018 5 5900 39 T-CELL EXHAUSTION IN ORGAN TRANSPLANTATION. EXHAUSTION OF T CELLS OCCURS IN RESPONSE TO LONG-TERM EXPOSURE TO SELF AND FOREIGN ANTIGENS. IT LIMITS T CELL CAPACITY TO PROLIFERATE AND PRODUCE CYTOKINES, LEADING TO AN IMPAIRED ABILITY TO CLEAR CHRONIC INFECTIONS OR ERADICATE TUMORS. T-CELL EXHAUSTION IS ASSOCIATED WITH A SPECIFIC TRANSCRIPTIONAL, EPIGENETIC, AND METABOLIC PROGRAM AND CHARACTERISTIC CELL SURFACE MARKERS' EXPRESSION. RECENT STUDIES HAVE BEGUN TO ELUCIDATE THE ROLE OF T-CELL EXHAUSTION IN TRANSPLANT. HIGHER LEVELS OF EXHAUSTED T CELLS HAVE BEEN ASSOCIATED WITH BETTER GRAFT FUNCTION IN KIDNEY TRANSPLANT RECIPIENTS. IN CONTRAST, REINVIGORATING EXHAUSTED T CELLS BY IMMUNE CHECKPOINT BLOCKADE THERAPIES, WHILE PROMOTING TUMOR CLEARANCE, INCREASES THE RISK OF ACUTE REJECTION. LYMPHOCYTE DEPLETION AND HIGH ALLOANTIGEN LOAD HAVE BEEN IDENTIFIED AS MAJOR DRIVERS OF T-CELL EXHAUSTION. THIS COULD ACCOUNT, AT LEAST IN PART, FOR THE REDUCED RATES OF ACUTE REJECTION IN ORGAN TRANSPLANT RECIPIENTS INDUCED WITH THYMOGLOBULIN AND FOR THE PRO-TOLEROGENIC EFFECTS OF A LARGE ORGAN SUCH AS THE LIVER. AMONG THE DRUGS THAT ARE WIDELY USED FOR MAINTENANCE IMMUNOSUPPRESSION, CALCINEURIN INHIBITORS HAVE A CONTRASTING INHIBITORY EFFECT ON EXHAUSTION OF T CELLS, WHILE THE INFLUENCE OF MTOR INHIBITORS IS STILL UNCLEAR. HARNESSING OR ENCOURAGING THE NATURAL PROCESSES OF EXHAUSTION MAY PROVIDE A NOVEL STRATEGY TO PROMOTE GRAFT SURVIVAL AND TRANSPLANTATION TOLERANCE. 2022 6 3013 22 GENETICS AND EPIGENETICS OF CHRONIC ALLOGRAFT DYSFUNCTION IN KIDNEY TRANSPLANTS. CHRONIC ALLOGRAFT DYSFUNCTION IS THE MOST COMMON CAUSE OF ALLOGRAFT LOST. CHRONIC ALLOGRAFT DYSFUNCTION HAPPENS AS A RESULT OF COMPLEX INTERACTIONS AT THE MOLECULAR AND CELLULAR LEVELS. GENETIC AND ENVIRONMENTAL FACTORS BOTH INFLUENCE THE EVOLUTION AND PROGRESSION OF THE CHRONIC ALLOGRAFT DYSFUNCTION. EPIGENETIC MODIFICATION COULD BE CONSIDERED AS A THERAPEUTICALLY MODIFIABLE ELEMENT TO PAUSE THE FIBROSIS PROCESS THROUGH NOVEL STRATEGIES. IN THIS REVIEW, THE PUBMED DATABASE WAS SEARCHED FOR ENGLISH-LANGUAGE ARTICLES ON THESE NEW AREAS. 2016 7 1048 34 CLINICAL EPIGENETICS AND ACUTE/CHRONIC REJECTION IN SOLID ORGAN TRANSPLANTATION: AN UPDATE. THE LACK OF A PRECISE STRATIFICATION ALGORITHM FOR PREDICTING PATIENTS AT HIGH RISK OF GRAFT REJECTION CHALLENGES THE CURRENT SOLID ORGAN TRANSPLANTATION (SOT) CLINICAL SETTING. IN FACT, THE ESTABLISHED BIOMARKERS FOR TRANSPLANTATION OUTCOMES ARE UNABLE TO ACCURATELY PREDICT THE ONSET TIME AND SEVERITY OF GRAFT REJECTION (ACUTE OR CHRONIC) AS WELL AS THE INDIVIDUAL RESPONSE TO IMMUNOSUPPRESSIVE DRUGS. THUS, IDENTIFYING NOVEL MOLECULAR PATHWAYS UNDERLYING EARLY IMMUNOLOGICAL RESPONSES WHICH CAN DAMAGE TRANSPLANT INTEGRITY IS NEEDED TO REACH PRECISION MEDICINE AND PERSONALIZED THERAPY OF SOT. DIRECT EPIGENETIC-SENSITIVE MECHANISMS, MAINLY DNA METHYLATION AND HISTONE MODIFICATIONS, MAY PLAY A RELEVANT ROLE FOR IMMUNE ACTIVATION AND LONG-TERM EFFECTS (E.G., ACTIVATION OF FIBROTIC PROCESSES) WHICH MAY BE TRANSLATED IN NEW NON-INVASIVE BIOMARKERS AND DRUG TARGETS. IN PARTICULAR, THE MEASURE OF DNA METHYLATION BY USING THE BLOOD-BASED "EPIGENETIC CLOCK" SYSTEM MAY BE AN ADDED VALUE TO THE DONOR ELIGIBILITY CRITERIA PROVIDING AN ESTIMATION OF THE HEART BIOLOGICAL AGE AS WELL AS A PREDICTIVE BIOMARKERS. BESIDES, MONITORING OF DNA METHYLATION CHANGES MAY AID TO PREDICT ACUTE VS CHRONIC GRAFT DAMAGE IN KIDNEY TRANSPLANTATION (KT) PATIENTS. FOR EXAMPLE, HYPERMETHYLATION OF GENES BELONGING TO THE NOTCH AND WNT PATHWAYS SHOWED A HIGHER PREDICTIVE VALUE FOR CHRONIC INJURY OCCURRING AT 12 MONTHS POST-KT WITH RESPECT TO ESTABLISHED CLINICAL PARAMETERS. DETECTING HIGHER CIRCULATING CELL-FREE DNA (CFDNA) FRAGMENTS CARRYING HEPATOCYTE-SPECIFIC UNMETHYLATED LOCI IN THE INTER-ALPHA-TRYPSIN INHIBITOR HEAVY CHAIN 4 (ITIH4), INSULIN LIKE GROWTH FACTOR 2 RECEPTOR (IGF2R), AND VITRONECTIN (VTN) GENES MAY BE USEFUL TO PREDICT ACUTE GRAFT INJURY AFTER LIVER TRANSPLANTATION (LT) IN SERUM SAMPLES. FURTHERMORE, HYPOMETHYLATION IN THE FORKHEAD BOX P3 (FOXP3) GENE MAY SERVE AS A MARKER OF INFILTRATING NATURAL TREG PERCENTAGE IN THE GRAFT PROVIDING THE ABILITY TO PREDICT ACUTE REJECTION EVENTS AFTER HEART TRANSPLANTATION (HTX). WE AIM TO UPDATE ON THE POSSIBLE CLINICAL RELEVANCE OF DNA METHYLATION CHANGES REGULATING IMMUNE-RELATED PATHWAYS UNDERLYING ACUTE OR CHRONIC GRAFT REJECTION IN KT, LT, AND HTX WHICH MIGHT BE USEFUL TO PREVENT, MONITOR, AND TREAT SOLID ORGAN REJECTION AT PERSONALIZED LEVEL. 2021 8 2286 28 EPIGENETIC REGULATION IN KIDNEY TRANSPLANTATION. KIDNEY TRANSPLANTATION IS A STANDARD CARE FOR END STAGE RENAL DISEASE, BUT IT IS ALSO ASSOCIATED WITH A COMPLEX PATHOGENESIS INCLUDING ISCHEMIA-REPERFUSION INJURY, INFLAMMATION, AND DEVELOPMENT OF FIBROSIS. OVER THE PAST DECADE, ACCUMULATING EVIDENCE HAS SUGGESTED A ROLE OF EPIGENETIC REGULATION IN KIDNEY TRANSPLANTATION, INVOLVING DNA METHYLATION, HISTONE MODIFICATION, AND VARIOUS KINDS OF NON-CODING RNAS. HERE, WE ANALYZE THESE RECENT STUDIES SUPPORTING THE ROLE OF EPIGENETIC REGULATION IN DIFFERENT PATHOLOGICAL PROCESSES OF KIDNEY TRANSPLANTATION, I.E., ISCHEMIA-REPERFUSION INJURY, ACUTE REJECTION, AND CHRONIC GRAFT PATHOLOGIES INCLUDING RENAL INTERSTITIAL FIBROSIS. FURTHER INVESTIGATION OF EPIGENETIC ALTERATIONS, THEIR PATHOLOGICAL ROLES AND UNDERLYING MECHANISMS IN KIDNEY TRANSPLANTATION MAY LEAD TO NEW STRATEGIES FOR THE DISCOVERY OF NOVEL DIAGNOSTIC BIOMARKERS AND THERAPEUTIC INTERVENTIONS. 2022 9 6522 33 TRANSCRIPTIONAL AND EPIGENETIC REGULATION OF T CELL HYPORESPONSIVENESS. NAIVE CD8(+) T CELLS DIFFERENTIATE INTO EFFECTOR AND MEMORY CYTOLYTIC T CELLS (CTLS) DURING AN ACUTE INFECTION. IN CONTRAST, IN SCENARIOS OF PERSISTENT ANTIGEN STIMULATION, SUCH AS CHRONIC INFECTIONS AND CANCER, ANTIGEN-SPECIFIC CTLS SHOW A GRADUAL DECREASE IN EFFECTOR FUNCTION, A PHENOMENON THAT HAS BEEN TERMED CD8(+) T CELL "EXHAUSTION" OR "DYSFUNCTION." ANOTHER HYPORESPONSIVE STATE, TERMED "ANERGY", IS OBSERVED WHEN T CELLS ARE ACTIVATED IN THE ABSENCE OF POSITIVE COSTIMULATORY SIGNALS. AMONG THE MANY NEGATIVE REGULATORS INDUCED IN HYPORESPONSIVE T CELLS ARE INHIBITORY CELL-SURFACE RECEPTORS, SUCH AS PD-1, LAG-3, CTLA-4, AND TIM-3; "CHECKPOINT BLOCKADE" THERAPIES THAT INVOLVE TREATMENT OF PATIENTS WITH CANCER WITH BLOCKING ANTIBODIES TO THOSE RECEPTORS SHOW CONSIDERABLE PROMISE IN THE CLINIC BECAUSE THE BLOCKING ANTIBODIES CAN MITIGATE HYPORESPONSIVENESS AND PROMOTE TUMOR REJECTION. IN THIS REVIEW, WE DESCRIBE RECENT ADVANCES IN OUR MOLECULAR UNDERSTANDING OF THESE HYPORESPONSIVE STATES. WE REVIEW EVIDENCE FOR THE INVOLVEMENT OF DIVERSE TRANSCRIPTION FACTORS, METABOLIC PROGRAMS, AND CHROMATIN ACCESSIBILITY CHANGES IN HYPORESPONSIVE T CELLS, AND WE DISCUSS HOW CHECKPOINT BLOCKADE THERAPIES AFFECT THE MOLECULAR PROGRAM OF CD8(+) T CELL EXHAUSTION. 2017 10 596 38 BET PROTEINS: AN APPROACH TO FUTURE THERAPIES IN TRANSPLANTATION. IN ORDER TO DEVELOP NEW EFFICIENT THERAPIES FOR ORGAN TRANSPLANTATION, IT IS ESSENTIAL TO ACQUIRE A COMPREHENSIVE KNOWLEDGE OF THE MOLECULAR MECHANISMS AND PROCESSES, SUCH AS IMMUNE ACTIVATION, CHRONIC INFLAMMATION, AND FIBROSIS, WHICH LEAD TO REJECTION AND LONG-TERM GRAFT LOSS. RECENT EFFORTS HAVE SHED SOME LIGHT ON THE EPIGENETIC REGULATION ASSOCIATED WITH THESE PROCESSES. IN THIS CONTEXT, THE BROMO AND EXTRATERMINAL (BET) FAMILY OF BROMODOMAIN PROTEINS (BRD2, BRD3, BRD4, AND BRDT) HAVE EMERGED AS MAJOR EPIGENETIC PLAYERS, CONNECTING CHROMATIN STRUCTURE WITH GENE EXPRESSION CHANGES. THESE PROTEINS RECOGNIZE ACETYLATED LYSINES IN HISTONES AND MASTER TRANSCRIPTION FACTORS TO RECRUIT REGULATORY COMPLEX AND, FINALLY, MODIFY THE TRANSCRIPTIONAL PROGRAM. RECENT STUDIES INDICATE THAT BET PROTEINS ARE ESSENTIAL IN THE NF-KB-MEDIATED INFLAMMATORY RESPONSE, DURING THE ACTIVATION AND DIFFERENTIATION OF TH17-IMMUNE CELLS, AND IN PROFIBROTIC PROCESSES. HERE, WE REVIEW THIS NEW BODY OF DATA AND HIGHLIGHT THE EFFICIENCY OF BET INHIBITORS IN SEVERAL MODELS OF DISEASES. THE PROMISING RESULTS OBTAINED FROM THESE PRECLINICAL MODELS INDICATE THAT IT MAY BE TIME TO TRANSLATE THESE OUTCOMES TO THE TRANSPLANTATION FIELD, WHERE EPIGENETICS WILL BE OF INCREASING VALUE IN THE COMING YEARS. 2017 11 1253 27 CURRENT PROBLEMS AND FUTURE DIRECTIONS OF TRANSFUSION-INDUCED ALLOIMMUNIZATION: SUMMARY OF AN NHLBI WORKING GROUP. IN APRIL 2010, A WORKING GROUP SPONSORED BY THE NATIONAL HEART, LUNG, AND BLOOD INSTITUTE WAS ASSEMBLED TO IDENTIFY RESEARCH STRATEGIES TO IMPROVE OUR UNDERSTANDING OF ALLOIMMUNIZATION CAUSED BY THE TRANSFUSION OF ALLOGENEIC BLOOD COMPONENTS AND TO EVALUATE POTENTIAL APPROACHES TO BOTH REDUCE ITS OCCURRENCE AND MANAGE ITS EFFECTS. SIGNIFICANT SEQUELAE OF ALLOIMMUNIZATION WERE DISCUSSED AND IDENTIFIED, INCLUDING DIFFICULTIES IN MAINTAINING CHRONIC TRANSFUSION OF RED BLOOD CELLS AND PLATELETS, HEMOLYTIC DISEASE OF THE NEWBORN, NEONATAL ALLOIMMUNE THROMBOCYTOPENIA, AND REJECTION OF TRANSPLANTED CELLS AND TISSUES. THE DISCUSSIONS RESULTED IN A CONSENSUS THAT IDENTIFIED KEY AREAS OF FUTURE RESEARCH AND DEVELOPMENTAL AREAS, INCLUDING GENETIC AND EPIGENETIC RECIPIENT FACTORS THAT REGULATE ALLOIMMUNIZATION, BIOCHEMICAL SPECIFICS OF TRANSFUSED PRODUCTS THAT AFFECT ALLOIMMUNIZATION, AND NOVEL TECHNOLOGIES FOR HIGH-THROUGHPUT GENOTYPING TO FACILITATE EXTENSIVE AND EFFICIENT ANTIGEN MATCHING BETWEEN DONOR AND RECIPIENT. ADDITIONAL AREAS OF IMPORTANCE INCLUDED ANALYSIS OF UNAPPRECIATED MEDICAL SEQUELAE OF ALLOIMMUNIZATION, SUCH AS CELLULAR IMMUNITY AND ITS EFFECT UPON TRANSPLANT AND AUTOIMMUNITY. IN ADDITION, SUPPORT FOR RESEARCH INFRASTRUCTURE WAS DISCUSSED, WITH AN EMPHASIS ON ENCOURAGING COLLABORATION AND SYNERGY OF ANIMAL MODELS BIOLOGY AND HUMAN CLINICAL RESEARCH. FINALLY, TRAINING FUTURE INVESTIGATORS WAS IDENTIFIED AS AN AREA OF IMPORTANCE. IN AGGREGATE, THIS COMMUNICATION PROVIDES A SYNOPSIS OF THE OPINIONS OF THE WORKING GROUP ON THE ABOVE ISSUES AND PRESENTS BOTH A LIST OF SUGGESTED PRIORITIES AND THE RATIONALE FOR THE TOPICS OF FOCUS. THE AREAS OF RESEARCH IDENTIFIED IN THIS REPORT REPRESENT POTENTIAL FERTILE GROUND FOR THE MEDICAL ADVANCEMENT OF PREVENTING AND MANAGING ALLOIMMUNIZATION IN ITS DIFFERENT FORMS AND MITIGATING THE CLINICAL PROBLEMS IT PRESENTS TO MULTIPLE PATIENT POPULATIONS. 2011 12 3670 35 INFLAMMAGING AND COMPLEMENT SYSTEM: A LINK BETWEEN ACUTE KIDNEY INJURY AND CHRONIC GRAFT DAMAGE. THE ABERRANT ACTIVATION OF COMPLEMENT SYSTEM IN SEVERAL KIDNEY DISEASES SUGGESTS THAT THIS PILLAR OF INNATE IMMUNITY HAS A CRITICAL ROLE IN THE PATHOPHYSIOLOGY OF RENAL DAMAGE OF DIFFERENT ETIOLOGIES. A GROWING BODY OF EXPERIMENTAL EVIDENCE INDICATES THAT COMPLEMENT ACTIVATION CONTRIBUTES TO THE PATHOGENESIS OF ACUTE KIDNEY INJURY (AKI) SUCH AS DELAYED GRAFT FUNCTION (DGF) IN TRANSPLANT PATIENTS. AKI IS CHARACTERIZED BY THE RAPID LOSS OF THE KIDNEY'S EXCRETORY FUNCTION AND IS A COMPLEX SYNDROME CURRENTLY LACKING A SPECIFIC MEDICAL TREATMENT TO ARREST OR ATTENUATE PROGRESSION IN CHRONIC KIDNEY DISEASE (CKD). RECENT EVIDENCE SUGGESTS THAT INDEPENDENTLY FROM THE INITIAL TRIGGER (I.E., SEPSIS OR ISCHEMIA/REPERFUSIONS INJURY), AN EPISODE OF AKI IS STRONGLY ASSOCIATED WITH AN INCREASED RISK OF SUBSEQUENT CKD. THE AKI-TO-CKD TRANSITION MAY INVOLVE A WIDE RANGE OF MECHANISMS INCLUDING SCAR-FORMING MYOFIBROBLASTS GENERATED FROM DIFFERENT SOURCES, MICROVASCULAR RAREFACTION, MITOCHONDRIAL DYSFUNCTION, OR CELL CYCLE ARREST BY THE INVOLVEMENT OF EPIGENETIC, GENE, AND PROTEIN ALTERATIONS LEADING TO COMMON FINAL SIGNALING PATHWAYS [I.E., TRANSFORMING GROWTH FACTOR BETA (TGF-BETA), P16 (INK4A) , WNT/BETA-CATENIN PATHWAY] INVOLVED IN RENAL AGING. RESEARCH IN RECENT YEARS HAS REVEALED THAT SEVERAL STRESSORS OR COMPLICATIONS SUCH AS REJECTION AFTER RENAL TRANSPLANTATION CAN LEAD TO ACCELERATED RENAL AGING WITH DETRIMENTAL EFFECTS WITH THE ESTABLISHMENT OF CHRONIC PROINFLAMMATORY CELLULAR PHENOTYPES WITHIN THE KIDNEY. DESPITE A GREATER UNDERSTANDING OF THESE MECHANISMS, THE ROLE OF COMPLEMENT SYSTEM IN THE CONTEXT OF THE AKI-TO-CKD TRANSITION AND RENAL INFLAMMAGING IS STILL POORLY EXPLORED. THE PURPOSE OF THIS REVIEW IS TO SUMMARIZE RECENT FINDINGS DESCRIBING THE ROLE OF COMPLEMENT IN AKI-TO-CKD TRANSITION. WE WILL ALSO ADDRESS HOW AND WHEN COMPLEMENT INHIBITORS MIGHT BE USED TO PREVENT AKI AND CKD PROGRESSION, THEREFORE IMPROVING GRAFT FUNCTION. 2020 13 5431 31 REGULATORY T CELLS: PATHOPHYSIOLOGICAL ROLES AND CLINICAL APPLICATIONS. INFLAMMATION AND IMMUNE RESPONSES AFTER TISSUE INJURY PLAY PIVOTAL ROLES IN THE RESOLUTION OF INFLAMMATION, TISSUE RECOVERY, FIBROSIS, AND REMODELING. REGULATORY T CELLS (TREGS) ARE RESPONSIBLE FOR IMMUNE TOLERANCE AND ARE USUALLY ACTIVATED IN SECONDARY LYMPHATIC TISSUES. ACTIVATED TREGS SUBSEQUENTLY REGULATE EFFECTOR T CELL AND DENDRITIC CELL ACTIVATION. FOR CLINICAL APPLICATIONS SUCH AS THE SUPPRESSION OF BOTH AUTOIMMUNE DISEASES AND THE REJECTION OF TRANSPLANTED ORGANS, METHODS TO GENERATE STABILIZED ANTIGEN-SPECIFIC TREGS ARE REQUIRED. FOR THIS PURPOSE, TRANSCRIPTIONAL AND EPIGENETIC REGULATION OF FOXP3 EXPRESSION HAS BEEN INVESTIGATED. IN ADDITION TO CONVENTIONAL TREGS, THERE ARE SOME TREGS THAT RESIDE IN TISSUES AND ARE CALLED TISSUE TREGS. TISSUE TREGS EXHIBIT TISSUE-SPECIFIC FUNCTIONS THAT CONTRIBUTE TO THE MAINTENANCE OF TISSUE HOMEOSTASIS AND REPAIR. SUCH TISSUE TREGS COULD ALSO BE USEFUL FOR TREG-BASED CELL THERAPY. WE RECENTLY DISCOVERED BRAIN TREGS THAT ACCUMULATE IN THE BRAIN DURING THE CHRONIC PHASE OF ISCHEMIC BRAIN INJURY. BRAIN TREGS RESEMBLE OTHER TISSUE TREGS, BUT ARE UNIQUE IN EXPRESSING NEURAL CELL-SPECIFIC GENES SUCH AS THE SEROTONIN RECEPTOR (HTR7); CONSEQUENTLY, BRAIN TREGS RESPOND TO SEROTONIN. HERE, WE DESCRIBE OUR EXPERIENCES IN THE USE OF TREGS TO SUPPRESS GRAFT-VERSUS-HOST DISEASE AND TO PROMOTE NEURAL RECOVERY AFTER STROKE. 2020 14 2615 34 EPIGENETICS: TIME TO TRANSLATE INTO TRANSPLANTATION. SUBSTANTIAL PROGRESS HAS BEEN MADE IN IDENTIFYING GENETIC LOCI ASSOCIATED WITH MULTIFACTORIAL DISORDERS, INCLUDING VARIANTS THAT SEEM TO IMPACT OUTCOMES FOLLOWING SOLID ORGAN TRANSPLANTATION. DESPITE THESE ADVANCES, MUCH OF THE HERITABILITY AND SUSCEPTIBILITY TO CHRONIC DISEASE PROCESSES REMAINS UNEXPLAINED. EPIGENETIC MODIFICATIONS MAY EXERT THEIR EFFECT INDEPENDENTLY OR COMPLEMENTARY TO GENETIC VARIANTS. EPIGENETIC MODIFICATIONS CAN CHANGE GENE EXPRESSION WITHOUT ALTERING THE DNA SEQUENCE. THESE MODIFICATIONS ARE DYNAMIC, POTENTIALLY HERITABLE, AND CAN BE INDUCED BY ENVIRONMENTAL STIMULI OR DRUGS. THE IMPACT OF EPIGENETIC PHENOMENA ON THE OUTCOMES OF ORGAN TRANSPLANTATION IS CURRENTLY POORLY UNDERSTOOD. EPIGENETIC MODIFICATIONS CAN OCCUR DURING PERIODS OF ILLNESS; THESE MAY PERSIST AND POTENTIALLY INFLUENCE ALLOGRAFT OUTCOMES. EPIGENETIC MECHANISMS INFLUENCE THE ACTIVATION, PROLIFERATION, AND DIFFERENTIATION OF THE IMMUNE CELLS INVOLVED IN ALLOGRAFT REJECTION. THE DONOR'S EPIGENOME MAY ALSO IMPACT TRANSPLANT SURVIVAL, AND INITIAL RESEARCH HAS DEMONSTRATED THAT PERITRANSPLANT CONDITIONS INDUCE RAPID EPIGENETIC MODIFICATION WITHIN THE ALLOGRAFT. FURTHER RESEARCH WILL HELP TO DEFINE THE IMPORTANCE OF EPIGENETIC MODIFICATIONS IN TRANSPLANTATION. THIS WILL POTENTIALLY LEAD TO THE IDENTIFICATION OF USEFUL BIOMARKERS AND THE DEVELOPMENT OF NOVEL PHARMACOTHERAPIES. THIS REVIEW EXPLORES THE NATURE OF EPIGENETIC MODIFICATION IN DISEASE AND THE EMERGING EVIDENCE FOR EPIGENETIC INFLUENCES ON ALLOGRAFT SURVIVAL. 2012 15 2367 24 EPIGENETIC REGULATION OF T CELL EXHAUSTION. CHRONIC ANTIGEN STIMULATION DURING VIRAL INFECTIONS AND CANCER CAN LEAD TO T CELL EXHAUSTION, WHICH IS CHARACTERIZED BY REDUCED EFFECTOR FUNCTION AND PROLIFERATION, AND THE EXPRESSION OF INHIBITORY IMMUNE CHECKPOINT RECEPTORS. RECENT STUDIES HAVE DEMONSTRATED THAT T CELL EXHAUSTION RESULTS IN WHOLESCALE EPIGENETIC REMODELING THAT CONFERS PHENOTYPIC STABILITY TO THESE CELLS AND PREVENTS T CELL REINVIGORATION BY CHECKPOINT BLOCKADE. HERE, WE REVIEW FOUNDATIONAL TECHNOLOGIES TO PROFILE THE EPIGENOME AT MULTIPLE SCALES, INCLUDING MAPPING THE LOCATIONS OF TRANSCRIPTION FACTORS AND HISTONE MODIFICATIONS, DNA METHYLATION AND THREE-DIMENSIONAL GENOME CONFORMATION. WE DISCUSS HOW THESE TECHNOLOGIES HAVE ELUCIDATED THE DEVELOPMENT AND EPIGENETIC REGULATION OF EXHAUSTED T CELLS AND FUNCTIONAL IMPLICATIONS ACROSS VIRAL INFECTION, CANCER, AUTOIMMUNITY AND ENGINEERED T CELL THERAPIES. FINALLY, WE COVER EMERGING MULTI-OMIC AND GENOME ENGINEERING TECHNOLOGIES, CURRENT AND UPCOMING OPPORTUNITIES TO APPLY THESE TO T CELL EXHAUSTION, AND THERAPEUTIC OPPORTUNITIES FOR T CELL ENGINEERING IN THE CLINIC. 2022 16 5806 34 STRATEGIES TO REINVIGORATE EXHAUSTED CD8(+) T CELLS IN TUMOR MICROENVIRONMENT. CD8(+) T CELL EXHAUSTION IS A STABLE DYSFUNCTIONAL STATE DRIVEN BY CHRONIC ANTIGEN STIMULATION IN THE TUMOR MICROENVIRONMENT (TME). DIFFERENTIATION OF EXHAUSTED CD8(+) T CELLS (CD8(+) TEXS) IS ACCOMPANIED BY EXTENSIVE TRANSCRIPTIONAL, EPIGENETIC AND METABOLIC REPROGRAMMING. CD8(+) TEXS ARE MAINLY CHARACTERIZED BY IMPAIRED PROLIFERATIVE AND CYTOTOXIC CAPACITY AS WELL AS THE INCREASED EXPRESSION OF MULTIPLE CO-INHIBITORY RECEPTORS. PRECLINICAL TUMOR STUDIES AND CLINICAL COHORTS HAVE DEMONSTRATED THAT T CELL EXHAUSTION IS FIRMLY ASSOCIATED WITH POOR CLINICAL OUTCOMES IN A VARIETY OF CANCERS. MORE IMPORTANTLY, CD8(+) TEXS ARE REGARDED AS THE MAIN RESPONDER TO IMMUNE CHECKPOINT BLOCKADE (ICB). HOWEVER, TO DATE, A LARGE NUMBER OF CANCER PATIENTS HAVE FAILED TO ACHIEVE DURABLE RESPONSES AFTER ICB. THEREFORE, IMPROVING CD8(+) TEXS MAY BE A BREAKTHROUGH POINT TO REVERSE THE CURRENT DILEMMA OF CANCER IMMUNOTHERAPY AND ELIMINATE CANCERS. STRATEGIES TO REINVIGORATE CD8(+) TEXS IN TME MAINLY INCLUDE ICB, TRANSCRIPTION FACTOR-BASED THERAPY, EPIGENETIC THERAPY, METABOLISM-BASED THERAPY AND CYTOKINE THERAPY, WHICH TARGET ON DIFFERENT ASPECTS OF EXHAUSTION PROGRESSION. EACH OF THEM HAS ITS ADVANTAGES AND APPLICATION SCOPE. IN THIS REVIEW, WE MAINLY FOCUS ON THE MAJOR ADVANCES OF CURRENT STRATEGIES TO REINVIGORATE CD8(+) TEXS IN TME. WE SUMMARIZE THEIR EFFICACY AND MECHANISMS, IDENTIFY THE PROMISING MONOTHERAPY AND COMBINED THERAPY AND PROPOSE SUGGESTIONS TO ENHANCE THE TREATMENT EFFICACY TO SIGNIFICANTLY BOOST ANTI-TUMOR IMMUNITY AND ACHIEVE BETTER CLINICAL OUTCOMES. 2023 17 5620 31 SCHRODINGER'S T CELLS: MOLECULAR INSIGHTS INTO STEMNESS AND EXHAUSTION. T CELL STEMNESS AND EXHAUSTION COEXIST AS TWO KEY CONTRASTING PHENOMENA DURING CHRONIC ANTIGEN STIMULATION, SUCH AS INFECTION, TRANSPLANT, CANCER, AND AUTOIMMUNITY. T CELL EXHAUSTION REFERS TO THE PROGRESSIVE LOSS OF EFFECTOR FUNCTION CAUSED BY CHRONIC ANTIGEN EXPOSURE. EXHAUSTED T (T(EX)) CELLS HIGHLY EXPRESS MULTIPLE INHIBITORY RECEPTORS AND EXHIBIT SEVERE DEFECTS IN CELL PROLIFERATION AND CYTOKINE PRODUCTION. THE TERM T CELL STEMNESS DESCRIBES THE STEM CELL-LIKE BEHAVIORS OF T CELLS, INCLUDING SELF-RENEWAL, MULTIPOTENCY, AND FUNCTIONAL PERSISTENCE. IT IS WELL ACCEPTED THAT NAIVE AND SOME MEMORY T CELL SUBSETS HAVE STEM CELL-LIKE PROPERTIES. WHEN INVESTIGATING THE EXHAUSTIVE DIFFERENTIATION OF T CELLS IN CHRONIC INFECTION AND CANCER, RECENT STUDIES HIGHLIGHTED THE STEMNESS OF "PRECURSORS OF EXHAUSTED" T (T(PEX)) CELLS PRIOR TO THEIR TERMINAL DIFFERENTIATION TO T(EX) CELLS. CLINICALLY SUCCESSFUL CHECKPOINT BLOCKADES FOR CANCER TREATMENT APPEAR TO INVIGORATE ANTITUMOR T(PEX) CELLS BUT NOT T(EX) CELLS. HERE WE DISCUSS THE TRANSCRIPTIONAL AND EPIGENETIC REGULATIONS OF T CELL STEMNESS AND EXHAUSTION, WITH A FOCUS ON HOW SYSTEMS IMMUNOLOGY WAS AND WILL BE UTILIZED TO DEFINE THE MOLECULAR BASIS UNDERLYING THE TRANSITION OF T(PEX) TO T(EX) CELLS. WE SUGGEST A "STEPWISE MODEL" OF T CELL STEMNESS AND EXHAUSTION, IN WHICH LOSS OF STEMNESS AND EXHAUSTION PROGRESSION ARE GRADUAL MULTI-STEP PROCESSES. WE PROVIDE PERSPECTIVES ON THE RESEARCH NEEDED TO DEFINE T CELL STEMNESS AND EXHAUSTION IN THE TRANSPLANTATION SETTING, IN WHICH ALLOGENIC T CELLS ARE ALSO CHRONICALLY EXPOSED TO ALLOANTIGENS. A BETTER UNDERSTANDING OF T CELL STEMNESS AND EXHAUSTION WILL SHED LIGHT ON DEVELOPING NOVEL STRATEGIES FOR IMMUNOTHERAPIES. 2021 18 5248 33 PROGRAMMED CELL DEATH 1-DIRECTED IMMUNOTHERAPY FOR ENHANCING T-CELL FUNCTION. T-CELL EXHAUSTION IS A UNIQUE STATE THAT APPEARS DURING MANY CHRONIC INFECTIONS AND CANCER AND IS CHARACTERIZED BY LOSS OF PROLIFERATIVE CAPACITY AND EFFECTOR FUNCTION. COMPLEX MECHANISMS ARE INVOLVED IN THIS T-CELL DYSFUNCTION BUT AN INHIBITORY RECEPTOR, PD-1, HAS BEEN IDENTIFIED AS A MAJOR REGULATOR OF T-CELL EXHAUSTION. BLOCKADE OF THE PD-1 PATHWAY CAN REINVIGORATE EXHAUSTED T CELLS, RESULTING IN BETTER CONTROL OF CHRONIC INFECTIONS AND CANCER. NOTABLY, RECENT CLINICAL STUDIES HAVE REVEALED THAT PD-1-DIRECTED IMMUNOTHERAPY IS HIGHLY EFFECTIVE IN CANCER PATIENTS, DEMONSTRATING THAT PD-1 IS A PROMISING THERAPEUTIC TARGET IN HUMANS. IN THIS REVIEW, WE SUMMARIZE OUR CURRENT UNDERSTANDING OF THE EPIGENETIC REGULATION OF PD-1 EXPRESSION IN T CELLS AND DISCUSS POTENTIAL COMBINATION THERAPY WITH PD-1 BLOCKADE TOWARD DEVELOPING MORE EFFECTIVE TREATMENT FOR CHRONIC INFECTIONS AND CANCER. 2013 19 4967 30 PATHOLOGICAL CONDITIONS RE-SHAPE PHYSIOLOGICAL TREGS INTO PATHOLOGICAL TREGS. CD4(+)FOXP3(+) REGULATORY T CELLS (TREGS) ARE A SUBSET OF CD4 T CELLS THAT PLAY AN ESSENTIAL ROLE IN MAINTAINING PERIPHERAL IMMUNE TOLERANCE, CONTROLLING ACUTE AND CHRONIC INFLAMMATION, ALLERGY, AUTOIMMUNE DISEASES, AND ANTI-CANCER IMMUNE RESPONSES. OVER THE PAST 20 YEARS, SIGNIFICANT PROGRESS HAS BEEN MADE SINCE TREGS WERE FIRST CHARACTERIZED IN 1995. MANY CONCEPTS AND PRINCIPLES REGARDING TREGS GENERATION, PHENOTYPIC FEATURES, SUBSETS (TTREGS, PTREGS, ITREGS, AND ITREG35), TISSUE SPECIFICITY (CENTRAL TREGS, EFFECTOR TREGS, AND TISSUE RESIDENT TREGS), HOMEOSTASIS (HIGHLY DYNAMIC AND APOPTOTIC), REGULATION OF TREGS BY RECEPTORS FOR PAMPS AND DAMPS, TREG PLASTICITY (RE-DIFFERENTIATION TO OTHER CD4 T HELPER CELL SUBSETS, TH1, TH2, TFH AND TH17), AND EPIGENETIC REGULATION OF TREGS PHENOTYPES AND FUNCTIONS HAVE BEEN INNOVATED. IN THIS CONCISE REVIEW, WE WANT TO BRIEFLY ANALYZE THESE EIGHT NEW PROGRESSES IN THE STUDY OF TREGS. WE HAVE ALSO PROPOSED FOR THE FIRST TIME A NOVEL CONCEPT THAT "PHYSIOLOGICAL TREGS" HAVE BEEN RE-SHAPED INTO "PATHOLOGICAL TREGS" IN VARIOUS PATHOLOGICAL ENVIRONMENTS. CONTINUING OF THE IMPROVEMENT IN OUR UNDERSTANDING ON THIS IMPORTANT CELLULAR COMPONENT ABOUT THE IMMUNE TOLERANCE AND IMMUNE SUPPRESSION, WOULD LEAD TO THE FUTURE DEVELOPMENT OF NOVEL THERAPEUTICS APPROACHES FOR ACUTE AND CHRONIC INFLAMMATORY DISEASES, ALLERGY, ALLOGENEIC TRANSPLANTATION-RELATED IMMUNITY, SEPSIS, AUTOIMMUNE DISEASES, AND CANCERS. 2015 20 790 18 CELLULAR AND MOLECULAR MECHANISMS OF CD8(+) T CELL DIFFERENTIATION, DYSFUNCTION AND EXHAUSTION. T CELLS FOLLOW A TRIPHASIC DISTINCT PATHWAY OF ACTIVATION, PROLIFERATION AND DIFFERENTIATION BEFORE BECOMING FUNCTIONALLY AND PHENOTYPICALLY "EXHAUSTED" IN SETTINGS OF CHRONIC INFECTION, AUTOIMMUNITY AND IN CANCER. EXHAUSTED T CELLS PROGRESSIVELY LOSE CANONICAL EFFECTOR FUNCTIONS, EXHIBIT ALTERED TRANSCRIPTIONAL NETWORKS AND EPIGENETIC SIGNATURES AND GAIN CONSTITUTIVE EXPRESSION OF A BROAD COINHIBITORY RECEPTOR SUITE. THIS REVIEW OUTLINES RECENT ADVANCES IN OUR UNDERSTANDING OF EXHAUSTED T CELL BIOLOGY AND EXAMINES CELLULAR AND MOLECULAR MECHANISMS BY WHICH A STATE OF DYSFUNCTION OR EXHAUSTION IS ESTABLISHED, AND MECHANISMS BY WHICH EXHAUSTED T CELLS MAY STILL CONTRIBUTE TO PATHOGEN OR TUMOUR CONTROL. FURTHER, THIS REVIEW DESCRIBES OUR UNDERSTANDING OF EXHAUSTED T CELL HETEROGENEITY AND OUTLINES THE MECHANISMS BY WHICH CHECKPOINT BLOCKADE DIFFERENTIALLY ENGAGES EXHAUSTED T CELL SUBSETS TO OVERCOME EXHAUSTION AND RECOVER T CELL FUNCTION. 2020