Harnessing Mechanisms of Immune Tolerance to Improve Outcomes in Solid Organ Transplantation: A Review.
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ABSTRACT:
SUBMITTER: Slepicka PF
PROVIDER: S-EPMC8222735 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Infectious complications remain a leading cause of morbidity and mortality after solid organ transplantation (SOT), and largely depend on the net state of immunosuppression achieved with current regimens. Cytomegalovirus (CMV) is a major opportunistic viral pathogen in this setting. The application of strategies of immunological monitoring in SOT recipients would allow tailoring of immunosuppression and prophylaxis practices according to the individual's actual risk of infection. Immune monitoring may be pathogen-specific or nonspecific. Nonspecific immune monitoring may rely on either the quantification of peripheral blood biomarkers that reflect the status of a given arm of the immune response (serum immunoglobulins and complement factors, lymphocyte sub-populations, soluble form of CD30), or on the functional assessment of T-cell responsiveness (release of intracellular adenosine triphosphate following a mitogenic stimulus). In addition, various methods are currently available for monitoring pathogen-specific responses, such as CMV-specific T-cell-mediated immune response, based on interferon-γ release assays, intracellular cytokine staining or main histocompatibility complex-tetramer technology. This review summarizes the clinical evidence to date supporting the use of these approaches to the post-transplant immune status, as well as their potential limitations. Intervention studies based on validated strategies for immune monitoring still need to be performed.
| S-EPMC4232060 | biostudies-other
Project description:BackgroundImmunosuppressive regimens associated with organ transplantation increase the risk of developing cancer. Transplant candidates and recipients with prostate cancer are often treated, even if low-risk features would ordinarily justify active surveillance.MethodsUsing SEER-Medicare, we identified 163 676 men aged 66 years and older diagnosed with nonmetastatic prostate cancer. History of solid organ transplant was identified using diagnosis or procedure codes. A propensity score-matched cohort was identified by matching transplanted men to nontransplanted controls by age, race, region, year, T-stage, grade, comorbidity, and cancer therapy. Fine-Gray competing risk models assessed associations between transplant status and prostate cancer-specific mortality (PCSM) and overall mortality (OM).ResultsWe identified 620 men (0.4%) with transplant up to 10 years before (n = 320) or 5 years after (n = 300) prostate cancer diagnosis and matched them to 3100 men. At 10 years, OM was 55.7% and PCSM was 6.0% in the transplant cohort compared with 42.4% (P < .001) and 7.6% (P = .70) in the nontransplant cohort, respectively. Adjusted models showed no difference in PCSM for transplanted men (hazard ratio = 0.88, 95% confidence interval = 0.61 to 1.27, P = .70) or differences by prostate cancer therapy. Among 334 transplanted men with T1-2N0, well or moderately differentiated "low-risk" prostate cancer, PCSM was similar for treated and untreated men (hazard ratio = 0.92, 95% confidence interval = 0.47 to 1.81).ConclusionsAmong men aged 66 years and older with prostate cancer, an organ transplant is associated with higher OM but no observable difference in PCSM. These findings suggest men with prostate cancer and previous or future organ transplantation should be managed per usual standards of care, including consideration of active surveillance for low-risk cancer characteristics.
| S-EPMC8453608 | biostudies-literature
Project description:Solid organ transplantation (SOT) following haematopoietic cell transplantation (HCT) is a rare event. Uncertainty exists whether such recipients are at higher risk of relapse of underlying haematological disease or at increased risk of developing infectious or immunological complications and malignancies following SOT. The experience at our referral organ transplantation center and the present literature of SOT (n?=?198) in recipients following previous HCT was systematically reviewed. Outcome analysis of 206 SOT recipients following HCT challenges the validity of the frequently stated comparable outcome with recipients without prior HCT. SOT recipients after HCT are younger and have a higher mortality and morbidity in comparison with "standard" recipients. Rejection rates for SOT recipients following HCT appear to be lower for all organs, except for liver transplantation. In the setting of liver transplantation following HCT, mortality for recipients of deceased donor grafts appears to be exceptionally high, although experience with grafts of living donors are favourable. Morbidity was mostly associated with infectious and malignant complications. Of note some SOT recipients who received solid organ donation from the same HCT donor were able to achieve successful withdrawal of immune suppression. Despite limited follow-up, recipients with prior HCT show a different course after SOT, necessitating attention and closer follow-up.
| S-EPMC7092162 | biostudies-literature
Project description:BackgroundThe number of Medicaid beneficiaries has increased under the Affordable Care Act, improving access to solid organ transplantation in this disadvantaged patient cohort. It is unclear what impact Medicaid expansion will have on transplantation outcomes. We performed a retrospective cohort analysis to measure the frequency and variation in Medicaid transplantation and post-transplantation survival in Medicaid patients.Study designAdult heart, lung, liver, and renal transplant recipients between 2002 and 2011 (n = 169,194) reported to the Scientific Registry of Transplant Recipients were identified. Transplant recipients were classified based on insurance status (private, Medicare or Medicaid). Outcomes measures included 5-year post-transplantation survival, summarized using Kaplan-Meier curves and compared with log-rank tests. Organ-specific Cox proportional hazards models were used to adjust for donor and recipient factors.ResultsMedicaid patients comprised 8.6% of all organ transplant recipients. Fewer transplantations were performed than expected among Medicaid beneficiaries for all organs except liver (liver: observed to expected ratio = 1.21; 95% CI, 0.68-1.90; heart: observed to expected ratio = 0.89; 95% CI, 0.44-1.49; lung: observed to expected ratio = 0.57; 95% CI, 0.22-1.06; renal: observed to expected ratio = 0.32; 95% CI, 0.08-0.72). Medicaid transplant recipients were listed with more severe organ failure and experienced shorter transplant wait times. Post-transplantation survival was lower in Medicaid patients compared with private insurance for all organs. Post-transplantation survival in Medicaid patients was similar to Medicare patients for heart, liver, and renal but lower in lung.ConclusionsMedicaid organ transplant beneficiaries had significantly lower survival compared with privately insured beneficiaries. The more severe organ failure among Medicaid beneficiaries at the time of listing, suggested a pattern of late referral, which might account for worse outcomes. Implementation of the Affordable Care Act gives the opportunity to develop the necessary infrastructure to ensure timely transplantation referrals and improve long-term outcomes in this vulnerable population.
| S-EPMC5252827 | biostudies-literature
Project description:ObjectiveTo compare the clinical efficacy and bioequivalence of generic immunosuppressive drugs in patients with solid organ transplants.DesignSystematic review and meta-analysis of all studies comparing generic with innovator immunosuppressive drugs.Data sourcesMedline and Embase from 1980 to September 2014.Review methodsA literature search was performed for all studies comparing a generic to an innovator immunosuppressive drug in solid organ transplantation. Two reviewers independently extracted data and assessed quality of studies. Meta-analyses of prespecified outcomes were performed when deemed appropriate. Outcomes included patient survival, allograft survival, acute rejection, adverse events and bioequivalence.Results1679 citations were screened, of which 50 studies met eligibility criteria (17 randomized trials, 15 non-randomized interventional studies, and 18 observational studies). Generics were compared with Neoral (cyclosporine) (32 studies), Prograf (tacrolimus) (12 studies), and Cellcept (mycophenolate mofetil) (six studies). Pooled analysis of randomized controlled trials in patients with kidney transplants that reported bioequivalence criteria showed that Neoral (two studies) and Prograf (three studies) were not bioequivalent with generic preparations according to criteria of the European Medicines Agency. The single Cellcept trial also did not meet bioequivalence. Acute rejection was rare but did not differ between groups. For Neoral, the pooled Peto odds ratio was 1.23 (95% confidence interval 0.64 to 2.36) for kidney randomized controlled trials and 0.66 (0.40 to 1.08) for observational studies. For kidney observational studies, the pooled Peto odds ratios were 0.98 (0.37 to 2.60) for Prograf and 0.49 (0.09 to 2.56) for Cellcept. Meta-analyses for non-renal solid organ transplants were not performed because of a lack of data.There were insufficient data reported on patient or graft survival. Pooling of results was limited by inconsistent study methods and reporting of outcomes. Many studies did not report standard criteria used to determine bioequivalence. While rates of acute rejection seemed similar and were relatively rare, few studies were designed to properly compare clinical outcomes. Most studies had short follow-up times and included stable patients without a history of rejection.ConclusionsHigh quality data showing bioequivalence and clinical efficacy of generic immunosuppressive drugs in patients with transplants are lacking. Given the serious consequences of rejection and allograft failure, well designed studies on bioequivalence and safety of generic immunosuppression in transplant recipients are needed.
| S-EPMC4476317 | biostudies-literature
Project description:Solid organ transplantation in the mouse is a powerful research tool that has provided a pathway to find important mechanistic insights into the regulation of allograft injury, allograft immunopathology, and transplant rejection/tolerance, and that has unique advantages over transplantation in larger species, due to the well characterization of mouse genome and availability of genetically modified animals. However, setup of mouse liver, heart and kidney transplantation is a technically demanding surgical procedure, especially the orthotopic liver transplantation in mouse. Here, we performed Microwell-based single cell RNA-seq of three mouse organ transplantation models (liver, heart and kidney). Comparison of lymphocytes, parenchyma cells and peripheral blood mononuclear cells in liver, heart and kidney revealed distinct immune microenvironment at acute rejection and tolerance state respectively. Single-cell transcriptome analysis of mouse allograft without immunosuppressive drugs provided rich resources to help understand functioning solid-organ transplantation in human.
2022-11-18 | GSE189069 | GEO
Project description:In the current era, one of the major factors limiting graft survival is chronic antibody-mediated rejection (ABMR), whilst patient survival is impacted by the effects of immunosuppression on susceptibility to infection, malignancy and atherosclerosis. IgG antibodies play a role in all of these processes, and many of their cellular effects are mediated by Fc gamma receptors (Fc?Rs). These surface receptors are expressed by most immune cells, including B cells, natural killer cells, dendritic cells and macrophages. Genetic variation in FCGR genes is likely to affect susceptibility to ABMR and to modulate the physiological functions of IgG. In this review, we discuss the potential role played by Fc?Rs in determining outcomes in solid organ transplantation, and how genetic polymorphisms in these receptors may contribute to variations in transplant outcome.
| S-EPMC5107199 | biostudies-literature
Project description:In recent decades, solid organ transplantation (SOT) has increased the survival and quality of life for patients with end-stage organ failure by providing a potentially long-term treatment option. Although the availability of organs for transplantation has increased throughout the years, the demand greatly outweighs the supply. One possible solution for this problem is to extend the potential donor pool by using extended criteria donors. However, organs from such donors are more prone to ischemia reperfusion injury (IRI) resulting in higher rates of delayed graft function, acute and chronic graft rejection and worse overall SOT outcomes. This can be overcome by further investigating donor preconditioning strategies, graft perfusion and storage and by finding novel therapeutic agents that could reduce IRI. relaxin (RLX) is a peptide hormone with antifibrotic, antioxidant, anti-inflammatory and cytoprotective properties. The main research until now focused on heart failure; however, several preclinical studies showed its potentials for reducing IRI in SOT. The aim of this comprehensive review is to overview currently available literature on the possible role of RLX in reducing IRI and its positive impact on SOT.
| S-EPMC7013572 | biostudies-literature
Project description:Purpose of reviewThe prevalence of end-stage organ disease is increasing among HIV-infected (HIV+) individuals. Individuals with well-controlled HIV on antiretroviral therapy (ART), without active opportunistic infections or cancer, and with specified minimum CD4 cell counts are appropriate transplant candidates. Infectious disease clinicians can improve access to transplantation for these patients and optimize management pre- and post-transplant.Recent findingsClinical trials and registry-based studies demonstrate excellent outcomes for select HIV+ kidney and liver transplant recipients with similar patient and graft survival as HIV-uninfected patients. Elevated allograft rejection rates have been observed in HIV+ individuals; this may be related to a dysregulated immune system or drug interactions. Lymphocyte-depleting immunosuppression has been associated with lower rejection rates without increased infections using national registry data. Hepatitis C virus (HCV) coinfection has been associated with worse outcomes, however improvements are expected with direct-acting antivirals.SummarySolid organ transplantation should be considered for HIV+ individuals with end-stage organ disease. Infectious disease clinicians can optimize ART to avoid pharmacoenhancers, which interact with immunosuppression. The timing of HCV treatment (pre- or post-transplant) should be discussed with the transplant team. Finally, organs from HIV+ donors can now be considered for HIV+ transplant candidates, within research protocols.
| S-EPMC6028051 | biostudies-literature
Project description:BackgroundThe effects of pediatric solid organ transplantation on cancer risk may differ from those observed in adult recipients. We described cancers in pediatric recipients and compared incidence to the general population.MethodsThe US transplant registry was linked to 16 cancer registries to identify cancer diagnoses among recipients <18 years old at transplant. Standardized incidence ratios (SIRs) were estimated by dividing observed cancer counts among recipients by expected counts based on the general population rates. Cox regression was used to estimate the associations between recipient characteristics and non-Hodgkin's lymphoma (NHL) risk.ResultsAmong 17 958 pediatric recipients, 392 cancers were diagnosed, of which 279 (71%) were NHL. Compared with the general population, incidence was significantly increased for NHL (SIR = 212, 95% confidence interval [CI] = 188-238), Hodgkin's lymphoma (SIR = 19, 95% CI = 13-26), leukemia (SIR = 4, 95% CI = 2-7), myeloma (SIR = 229, 95% CI = 47-671), and cancers of the liver, soft tissue, ovary, vulva, testis, bladder, kidney, and thyroid. NHL risk was highest during the first year after transplantation among recipients <5 years old at transplant (SIR = 313), among recipients seronegative for Epstein-Barr virus (EBV) at transplant (SIR = 446), and among intestine transplant recipients (SIR = 1280). In multivariable analyses, seronegative EBV status, the first year after transplantation, intestine transplantation, and induction immunosuppression were independently associated with higher NHL incidence.ConclusionsPediatric recipients have a markedly increased risk for many cancers. NHL constitutes the majority of diagnosed cancers, with the highest risk occurring in the first year after transplantation. NHL risk was high in recipients susceptible to primary EBV infection after transplant and in intestine transplant recipients, perhaps due to EBV transmission in the donor organ.
| S-EPMC5404730 | biostudies-literature