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1.
Clin Transplant ; 37(11): e15074, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37534547

RESUMO

While kidney transplantation (KTx) has traditionally required lifelong immunosuppression, an investigational stem cell therapy, FCR001, has been demonstrated to induce tolerance and eliminate the need for immunosuppression through the establishment of persistent mixed chimerism in a phase 2 clinical study. Real-world evidence (RWE) methods were employed to compare the safety and efficacy of non-myeloablative conditioning with FCR001 with standard of care [SOC] immunosuppression in a retrospective single-center analysis of outcomes among propensity score matched living-donor KTx receiving SOC (n = 144) or FCR001 (n = 36). Among the FCR001 recipients, 26 (72%) developed persistent chimerism allowing durable elimination of all immunosuppression. There was no significant difference in the composite primary endpoint (biopsy-proven acute rejection [BPAR], graft loss, or death) at 60 months (FCR001 27.8%, n = 10 and SOC 28.5%, n = 41; p = .9). FCR001 recipients demonstrated superior kidney function at 5 years (estimated glomerular filtration rate [eGFR] [mean ± standard deviation]: 64.1 ± 15.3) compared to SOC (51.7 ± 18.8; p = .02). At 5 years, FCR001 recipients experienced fewer complications including new-onset diabetes post-transplant, although two patients developed graft versus host disease. In conclusion, RWE demonstrated that KTx combined with non-myeloablative conditioning and FCR001 resulting in superior kidney function without increasing the risk of rejection, graft loss, or death among patients off immunosuppression.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Rim , Humanos , Transplante de Rim/efeitos adversos , Estudos Retrospectivos , Terapia de Imunossupressão , Tolerância Imunológica , Imunossupressores/uso terapêutico , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/prevenção & controle
2.
Am J Transplant ; 21(1): 21-31, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32529725

RESUMO

The International Workshop on Clinical Transplant Tolerance is a biennial meeting that aims to provide an update on the progress of studies of immunosuppression minimization or withdrawal in solid organ transplantation. The Fourth International Workshop on Clinical Tolerance was held in Pittsburgh, Pennsylvania, September 5-6, 2019. This report is a summary of presentations on the status of clinical trials designed to minimize or withdraw immunosuppressive drugs in kidney, liver, and lung transplantation without subsequent evidence of rejection. All protocols had in common the use of donor or recipient cell therapy combined with organ transplantation. The workshop also included presentations of mechanistic studies designed to improve understanding of the cellular and molecular basis of tolerance and to identify potential predictors/biomarkers of tolerance. Strategies to enhance the safety of hematopoietic cell transplantation and to improve patient selection/risk stratification for clinical trials were also discussed.


Assuntos
Transplante de Órgãos , Tolerância ao Transplante , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/prevenção & controle , Humanos , Tolerância Imunológica , Terapia de Imunossupressão , Imunossupressores , Pennsylvania
3.
Curr Opin Nephrol Hypertens ; 30(1): 63-74, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33186221

RESUMO

PURPOSE OF REVIEW: Immunological factors are a major cause of kidney allograft loss. Calcineurin inhibitors (CNIs) have improved short-term kidney allograft survival; however, they in turn contribute to long-term kidney allograft loss from chronic CNI nephrotoxicity. Tolerance induction in transplantation can avoid the long-term adverse effects of immunosuppressive medications. This review aims to critically discuss recent efforts in inducing transplantation tolerance. RECENT FINDINGS: Tolerance induction mediated by chimerism has shown some promise in minimizing or even complete withdrawal of immunosuppressive treatments in kidney allograft recipients. There has been a number of approaches as varied as the number of centres conducting these trials. However, they can be grouped into those mediated by transient microchimerism and those facilitated by more stable macro or full donor chimerism. The success rates in terms of long-term drug-free graft survival has been limited in microchimerism-mediated tolerance induction approaches. Mixed macrochimerism of less than 50% donor may be unstable with mostly the recipient's native immune system overpowering the donor chimeric status.Tolerance induction leading to chimerism has been limited to living donor kidney transplantation and additional long-term outcomes are required. Furthermore, immune monitoring after tolerance induction has faced a limitation in studying due to a lack of sufficient study participants and appropriate study controls. SUMMARY: Tolerance induction is one of several strategies used to prolong kidney allograft survival, but it has not been routinely utilized in clinical practice. However, future applications from the trials to clinical practice remain limited to living donor kidney transplantation. Once further data regarding tolerance inductions exist and practicality becomes widely accepted, tolerance induction may shift the paradigm in the field of kidney transplantation to achieve the best possible outcome of 'One Organ for Life'.


Assuntos
Quimerismo , Sobrevivência de Enxerto , Tolerância Imunológica , Transplante de Rim , Insuficiência Renal Crônica/cirurgia , Aloenxertos/imunologia , Ensaios Clínicos como Assunto , Previsões , Facilitação Imunológica de Enxerto/métodos , Facilitação Imunológica de Enxerto/tendências , Sobrevivência de Enxerto/efeitos dos fármacos , Sobrevivência de Enxerto/imunologia , Humanos , Tolerância Imunológica/efeitos dos fármacos , Tolerância Imunológica/imunologia , Imunossupressores/efeitos adversos , Imunossupressores/imunologia , Imunossupressores/uso terapêutico , Rim/imunologia , Rim/cirurgia , Transplante de Rim/efeitos adversos , Doadores Vivos , Condicionamento Pré-Transplante , Tolerância ao Transplante/efeitos dos fármacos , Tolerância ao Transplante/imunologia
4.
Am J Transplant ; 20(2): 348-354, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31675469

RESUMO

In 2017, the American Society of Transplantation (AST) launched the Outstanding Questions in Transplantation Research forum to stimulate a community-wide discussion of how the field is evolving and to help identify areas where a better dialogue between clinicians and researchers could result in great advancements. Tolerance emerged as a topic of great interest to the AST community. This minireview provides an overview of clinical transplantation tolerance. Historical background followed by a review of the current status of attempts to establish tolerance in the clinic, highlighting the dynamic online discussion surrounding this important topic from the AST Transplantation Research forum, is provided.


Assuntos
Rejeição de Enxerto/prevenção & controle , Imunossupressores/uso terapêutico , Tolerância ao Transplante , Biomarcadores/metabolismo , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/imunologia , Humanos
5.
J Am Soc Nephrol ; 29(2): 423-433, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29191961

RESUMO

The modern immunosuppression regimen has greatly improved short-term allograft outcomes but not long-term allograft survival. Complications associated with immunosuppression, specifically nephrotoxicity and infection risk, significantly affect graft and patient survival. Inducing and understanding pathways underlying clinical tolerance after transplantation are, therefore, necessary. We previously showed full donor chimerism and immunosuppression withdrawal in highly mismatched allograft recipients using a bioengineered stem cell product (FCRx). Here, we evaluated the gene expression and microRNA expression profiles in renal biopsy samples from tolerance-induced FCRx recipients, paired donor organs before implant, and subjects under standard immunosuppression (SIS) without rejection and with acute rejection. Unlike allograft samples showing acute rejection, samples from FCRx recipients did not show upregulation of T cell- and B cell-mediated rejection pathways. Gene expression pathways differed slightly between FCRx samples and the paired preimplantation donor organ samples, but most of the functional gene networks overlapped. Notably, compared with SIS samples, FCRx samples showed upregulation of genes involved in pathways, like B cell receptor signaling. Additionally, prediction analysis showed inhibition of proinflammatory regulators and activation of anti-inflammatory pathways in FCRx samples. Furthermore, integrative analyses (microRNA and gene expression profiling from the same biopsy sample) identified the induction of regulators with demonstrated roles in the downregulation of inflammatory pathways and maintenance of tissue homeostasis in tolerance-induced FCRx samples compared with SIS samples. This pilot study highlights the utility of molecular intragraft evaluation of pathways related to FCRx-induced tolerance and the use of integrative analyses for identifying upstream regulators of the affected downstream molecular pathways.


Assuntos
Rejeição de Enxerto/genética , Sobrevivência de Enxerto/genética , Transplante de Células-Tronco Hematopoéticas , Transplante de Rim , MicroRNAs/genética , Tolerância ao Transplante/genética , Tolerância ao Transplante/imunologia , Adulto , Idoso , Linfócitos B/imunologia , Quimerismo , Regulação para Baixo , Feminino , Expressão Gênica , Ontologia Genética , Humanos , Terapia de Imunossupressão , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Período Pós-Operatório , Período Pré-Operatório , RNA Mensageiro/metabolismo , Transdução de Sinais/genética , Linfócitos T/imunologia , Transcriptoma , Transplante Homólogo , Regulação para Cima , Adulto Jovem
6.
J Am Soc Nephrol ; 28(7): 1960-1972, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28465379

RESUMO

Renal transplantation is the renal replacement modality of choice for suitable candidates with advanced CKD or ESRD. Prevention of rejection, however, requires treatment with nonspecific pharmacologic immunosuppressants that carry both systemic and nephrologic toxicities. Use of a patient's own suppressive regulatory T cells (Tregs) is an attractive biologic approach to reduce this burden. Here, we review the immunologic underpinnings of Treg therapy and technical challenges to developing successful cell therapy. These issues include the selection of appropriate Treg subsets, ex vivo Treg expansion approaches, how many Tregs to administer and when, and how to care for patients after Treg administration.


Assuntos
Rejeição de Enxerto/prevenção & controle , Terapia de Imunossupressão/métodos , Transplante de Rim , Linfócitos T Reguladores/transplante , Animais , Terapia Baseada em Transplante de Células e Tecidos/métodos , Ensaios Clínicos como Assunto , Humanos , Linfócitos T Reguladores/imunologia , Imunologia de Transplantes
7.
Curr Opin Organ Transplant ; 20(1): 57-63, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25522139

RESUMO

PURPOSE OF REVIEW: To describe the clinical outcomes and science behind a CD8/TCR facilitating cell-based hematopoietic stem cell transplant approach (termed FCRx) to induce tolerance to renal allografts without graft-versus-host disease (GVHD) and avoidance of long-term immunosuppressant drugs in living donor kidney transplant recipients. RECENT FINDINGS: Successful solid organ transplantation currently requires the life-long use of medications to suppress the immune system to prevent transplant rejection. Drug-based immunosuppression significantly increases the risk of infection and cancer, as well as being very costly. Development of new therapies to minimize or eliminate entirely the need for antirejection drugs is of great interest to the transplant community. Therapeutic cell transfer for the control of the human immune system represents a compelling approach to reduce or eliminate the need for antirejection drugs. SUMMARY: Establishment of durable hematopoietic macrochimerism under nonmyeloablative conditioning is achievable in mismatched recipients using facilitating cells and stem cells obtained from donor mobilized peripheral blood mononuclear cells. Persistently chimeric recipients developed donor-specific tolerance and were weaned off of immunosuppressive drugs over 12 months. They maintained stable renal function without development of acute or chronic GVHD.


Assuntos
Rejeição de Enxerto/imunologia , Doença Enxerto-Hospedeiro/imunologia , Células-Tronco Hematopoéticas/imunologia , Tolerância Imunológica/imunologia , Transplante de Rim , Animais , Transplante de Células-Tronco Hematopoéticas , Humanos
8.
J Am Soc Nephrol ; 24(9): 1376-85, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23787913

RESUMO

The ability to achieve immunologic tolerance after transplantation is a therapeutic goal. Here, we report interim results from an ongoing trial of tolerance in HLA-identical sibling renal transplantation. The immunosuppressive regimen included alemtuzumab induction, donor hematopoietic stem cells, tacrolimus/mycophenolate immunosuppression converted to sirolimus, and complete drug withdrawal by 24 months post-transplantation. Recipients were considered tolerant if they had normal biopsies and renal function after an additional 12 months without immunosuppression. Of the 20 recipients enrolled, 10 had at least 36 months of follow-up after transplantation. Five of these 10 recipients had immunosuppression successfully withdrawn for 16-36 months (tolerant), 2 had disease recurrence, and 3 had subclinical rejection in protocol biopsies (nontolerant). Microchimerism disappeared after 1 year, and CD4(+)CD25(high)CD127(-)FOXP3(+) regulatory T cells and CD19(+)IgD/M(+)CD27(-) B cells were increased through 5 years post-transplantation in both tolerant and nontolerant recipients. Immune/inflammatory gene expression pathways in the peripheral blood and urine, however, were differentially downregulated between tolerant and nontolerant recipients. In summary, interim results from this trial of tolerance in HLA-identical renal transplantation suggest that predictive genomic biomarkers, but not immunoregulatory phenotyping, may be able to discriminate tolerant from nontolerant patients.


Assuntos
DNA/genética , Genoma/genética , Antígenos HLA/genética , Antígenos HLA/imunologia , Tolerância Imunológica/imunologia , Transplante de Rim/imunologia , Adulto , Biomarcadores , Biópsia , Quimerismo , Feminino , Seguimentos , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Transplante de Células-Tronco Hematopoéticas , Humanos , Imunossupressores/uso terapêutico , Rim/patologia , Transplante de Rim/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
9.
Front Immunol ; 15: 1366972, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38455047

RESUMO

Introduction: Donor hematopoietic stem cell (DHSC) infusions are increasingly being studied in transplant patients for tolerance induction. Methods: To analyze the fate of infused DHSCs in patients, we developed an in vitro culture system utilizing CD34+DHSCs stimulated with irradiated allogeneic cells in cytokine supplemented medium long-term. Results: Flow cytometric analyses revealed loss of the CD34 marker and an increase in CD33+ myeloid and CD3+ T-cell proportion by 10.4% and 72.7%, respectively, after 21 days in culture. T-cells primarily expressed TcR-αß and were of both CD4+ and CD8+ subsets. Approximately 80% of CD3+ T cells lacked expression of the co-stimulatory receptor CD28. The CD4+ compartment was predominated by CD4+CD25+CD127-FOXP3+ Tregs (>50% CD4+CD127- compartment) with <1% of all leukocytes exhibiting a CD4+CD127+ phenotype. Molecular analyses for T-cell receptor excision circles showed recent and increased numbers of TcR rearrangements in generated T cells over time suggesting de novo differentiation from DHSCs. CD33+ myeloid cells mostly expressed HLA-DR, but lacked expression of co-stimulatory receptors CD80 and CD83. When studied as modulators in primary mixed lymphocyte reactions where the cells used to stimulate the DHSC were used as responders, the DHSC-lines and their purified CD8+, CD4+, CD33+ and linage negative subsets inhibited the responses in a dose-dependent and non-specific fashion. The CD8+ cell-mediated inhibition was due to direct lysis of responder cells. Discussion: Extrapolation of these results into the clinical situation would suggest that DHSC infusions into transplant recipients may generate multiple subsets of donor "chimeric" cells and promote recipient Treg development that could regulate the anti-donor immune response in the periphery. These studies have also indicated that T cell maturation can occur in vitro in response to allogeneic stimulation without the pre-requisite of a thymic-like environment or NOTCH signaling stimulatory cell line.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas , Adulto , Humanos , Linfócitos T CD8-Positivos , Antígenos CD34 , Receptores de Antígenos de Linfócitos T
10.
Front Immunol ; 15: 1377535, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38601147

RESUMO

Introduction: We investigated the potential role of HLA molecular mismatches (MM) in achieving stable chimerism, allowing for donor-specific tolerance in patients undergoing combined living donor kidney and hematopoietic stem cell transplantation (HSCT). Methods: All patients with available DNA samples (N=32) who participated in a phase 2 clinical trial (NCT00498160) where they received an HLA mismatched co-transplantation of living donor kidney and facilitating cell-enriched HSCT were included in this study. High-resolution HLA genotyping data were used to calculate HLA amino acid mismatches (AAMM), Eplet MM, three-dimensional electrostatic mismatch scores (EMS-3D), PIRCHE scores, HLA-DPB1 T-cell epitope group MM, HLA-B leader sequence MM, and KIR ligands MM between the donor and recipient in both directions. HLA MM were analyzed to test for correlation with the development of chimerism, graft vs. host disease (GvHD), de novo DSA, and graft rejection. Results: Follow-up time of this cohort was 6-13.5 years. Of the 32 patients, 26 developed high-level donor or mixed stable chimerism, followed by complete withdrawal of immunosuppression (IS) in 25 patients. The remaining six of the 32 patients had transient chimerism or no engraftment and were maintained on IS (On-IS). In host versus graft direction, a trend toward higher median number of HLA-DRB1 MM scores was seen in patients On-IS compared to patients with high-level donor/mixed chimerism, using any of the HLA MM modalities; however, initial statistical significance was observed only for the EMS-3D score (0.45 [IQR, 0.30-0.61] vs. 0.24 [IQR, 0.18-0.36], respectively; p=0.036), which was lost when applying the Bonferroni correction. No statistically significant differences between the two groups were observed for AAMM, EMS-3D, Eplet MM, and PIRCHE-II scores calculated in graft versus host direction. No associations were found between development of chimerism and GvHD and non-permissive HLA-DPB1 T-cell epitope group MM, HLA-B leader sequence, and KIR ligands MM. Conclusion: Our results suggest an association between HLA-DRB1 molecular mismatches and achieving stable chimerism, particularly when electrostatic quality of the mismatch is considered. The non-permissive HLA-DPB1 T-cell epitope group, HLA-B leader sequence, and KIR ligands MM do not predict chimerism and GvHD in this combined kidney/HSCT transplant patient cohort. Further work is needed to validate our findings. Clinical trial registration: https://clinicaltrials.gov/study/NCT00498160, identifier NCT00498160.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Humanos , Doadores Vivos , Epitopos de Linfócito T , Cadeias HLA-DRB1 , Teste de Histocompatibilidade , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Doença Enxerto-Hospedeiro/etiologia , Rim , Antígenos HLA-B
11.
Front Immunol ; 14: 1270300, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37868962

RESUMO

Despite the advances in therapeutic interventions, solid organ transplantation (SOT) remains the "gold standard" treatment for patients with end-stage organ failure. Recently, vascularized composite allotransplantation (VCA) has reemerged as a feasible treatment option for patients with complex composite tissue defects. In both SOT and VCA, ischemia reperfusion injury (IRI) is inevitable and is a predominant factor that can adversely affect transplant outcome by potentiating early graft dysfunction and/or graft rejection. Restoration of oxygenated blood supply to an organ which was previously hypoxic or ischemic for a period of time triggers cellular oxidative stress, production of both, pro-inflammatory cytokines and chemokines, infiltration of innate immune cells and amplifies adaptive alloimmune responses in the affected allograft. Currently, Food and Drug Administration (FDA) approved drugs for the treatment of IRI are unavailable, therefore an efficacious therapeutic modality to prevent, reduce and/or alleviate allograft damages caused by IRI induced inflammation is warranted to achieve the best-possible transplant outcome among recipients. The tolerogenic capacity of CD4+CD25+FOXP3+ regulatory T cells (Tregs), have been extensively studied in the context of transplant rejection, autoimmunity, and cancer. It was not until recently that Tregs have been recognized as a potential cell therapeutic candidate to be exploited for the prevention and/or treatment of IRI, owing to their immunomodulatory potential. Tregs can mitigate cellular oxidative stress, produce anti-inflammatory cytokines, promote wound healing, and tissue repair and prevent the infiltration of pro-inflammatory immune cells in injured tissues. By using strategic approaches to increase the number of Tregs and to promote targeted delivery, the outcome of SOT and VCA can be improved. This review focuses on two sections: (a) the therapeutic potential of Tregs in preventing and mitigating IRI in the context of SOT and VCA and (b) novel strategies on how Tregs could be utilized for the prevention and/or treatment of IRI.


Assuntos
Aloenxertos , Traumatismo por Reperfusão , Linfócitos T Reguladores , Humanos , Citocinas , Fatores de Transcrição Forkhead
12.
Am J Clin Pathol ; 159(3): 255-262, 2023 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-36626677

RESUMO

BACKGROUND: Improvement of liver transplantation (LT) outcomes requires better understanding of factors affecting survival. The presence of RBC alloantibodies (RBCAs) on survival in LT recipients was evaluated. METHODS: This study was a single-center, retrospective cohort study reviewing transfusion records and all-cause mortality between 2002 and 2021. RESULTS: Between 2002 and 2021, 2079 LTs were completed, 1,396 of which met inclusion criteria (1,305 RBCA negative; 91 RBCA positive [6.5%]). The cohorts were similar in age (mean [range], 55.8 [17-79] years vs 56.8 [25-73] years; P = .41, respectively) or sex (RBCA negative, 859 [65%] men and 446 [35%] women vs RBCA positive, 51 [56%] men and 40 [44%] women; P = .0684). Of 132 RBCAs detected, 10 were most common were to E (27.27%), Jka (15.91%), K (9.09%), C (8.33%), M (6.06%), D (5.3%), Fya (4.55%), e (2.27%), c (2.27%), and Jkb (2.27%). Twenty-seven patients (29.7%) had more than 1 RBCA; the most common combinations were C with Jka (7.4%) and E with Dia (7.4%). All-cause mortality was increased in men (men, 14.45 years vs women, 17.27 years; P = .0266) and patients 65 years of age and older (≥65 years of age, 10.21 years vs <64 years of age, 17.22 years; P < .0001). The presence of RBCA (≥1) did not affect all-cause mortality (RBCA negative, 14.17 years vs RBCA positive, 15.29 years; P = .4367). The top 5 causes of death were infection (11.9%), primary malignancy (solid) (10.8%), recurrent malignancy (10.5%), cardiovascular arrest (7.1%), and pulmonary insufficiency/respiratory failure (5.7%). CONCLUSIONS: Survival in RBCA-positive LT recipients is no different from that in RBCA-negative LT recipients.


Assuntos
Transplante de Fígado , Masculino , Humanos , Feminino , Criança , Adolescente , Pessoa de Meia-Idade , Estudos Retrospectivos , Recidiva Local de Neoplasia , Eritrócitos , Transfusão de Sangue , Isoanticorpos , Transplantados
13.
Transplantation ; 107(10): e257-e268, 2023 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-37370204

RESUMO

BACKGROUND: Thirty-seven patients have received a living-donor kidney transplant in a phase 2 study designed to induce tolerance with facilitated allogeneic hematopoietic stem cell transplant. The study protocol is based on tolerogenic CD8 + /T-cell receptor - facilitating cells (FCR001; also including hematopoietic stem cells and αß-T-cell receptor + T cells) and low-dose, nonmyeloablative conditioning. Persistent chimerism allowing full immunosuppression (IS) withdrawal was achieved in 26 patients (time off IS 36-123 mo). METHODS: We evaluated biomarkers of tolerance through urinary cell mRNA profiling and immunocompetence to respond to vaccination in these patients. We also assessed kidney function and metabolic parameters compared with standard-of-care patients on IS. RESULTS: Persistently chimeric patients retained chimerism after removal of IS and remained rejection free without donor HLA-specific antibody development. The presence of donor chimerism at >50% correlated with a signature of tolerance in urinary cell mRNA profiles, with a uniquely elevated increase in the ratio of cytotoxic T lymphocyte-associated protein 4 to granzyme B mRNA. Tolerance was associated with protection from recurrence of immune-mediated causes of kidney disease. Tolerant participants were safely vaccinated, developed protective immune responses, and did not lose chimerism after vaccination. When compared with kidney transplant recipients treated with standard IS, tolerant participants showed stable kidney function and reduced medication use for hypertension and hyperlipidemia. CONCLUSIONS: These results suggest that elimination of IS has distinct advantages in living-donor kidney allograft recipients.


Assuntos
Tolerância Imunológica , Condicionamento Pré-Transplante , Humanos , Condicionamento Pré-Transplante/métodos , Terapia de Imunossupressão , Rim , Biomarcadores , Imunocompetência , Aloenxertos , Tolerância ao Transplante , Quimeras de Transplante
14.
Front Immunol ; 13: 1055466, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36466912

RESUMO

Regulatory T cells (Tregs) are critical for tolerance in humans. The exact mechanisms by which the loss of peripheral tolerance leads to the development of autoimmunity and the specific role Tregs play in allograft tolerance are not fully understood; however, this population of T cells presents a unique opportunity in the development of targeted therapeutics. In this review, we discuss the potential roles of Foxp3+ Tregs in the development of tolerance in transplantation and autoimmunity, and the available data regarding their use as a treatment modality.


Assuntos
Autoimunidade , Transplante de Órgãos , Humanos , Linfócitos T Reguladores , Tolerância Imunológica , Transplante de Órgãos/efeitos adversos , Tolerância a Medicamentos , Fatores de Transcrição , Fatores de Transcrição Forkhead
15.
Curr Opin Organ Transplant ; 16(4): 345-52, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21666474

RESUMO

PURPOSE OF REVIEW: Infusions of bone marrow-derived cells together with 'space making' continue to be tested in clinical organ transplant tolerance protocols. These trials are based on the hypothesis that this might produce initial multilineage chimerism. There is some evidence that this in turn induces regulatory cells that control alloimmunity. Although a wealth of knowledge is available from animal models, this review deals with what we know or can speculate about donor bone marrow cells and chimerism in human organ transplantation. RECENT FINDINGS: Calcineurin inhibitors are employed in most of these protocols to blunt the initial immune response. One protocol also has a stepwise regulatory cell generating treatment with sirolimus before total withdrawal. A number of donor chimeric lineages including stem cells, dendritic cells, myeloid precursors, and various lymphoid subpopulations have been described. Currently, it is recognized that the nature of cells that make up the chimerism could influence graft rejection versus acceptance. Tolerogenic donor chimeric cells may also generate regulatory subsets, thus controlling alloimmunity on two fronts. SUMMARY: It might be speculated that prolonged and sustained regulation or possible anergy induced by chimerism may eventually lead to clonal deletion, thereby bringing about classical immunologic tolerance.


Assuntos
Transplante de Medula Óssea , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto , Transplante de Órgãos , Quimeras de Transplante , Tolerância ao Transplante , Deleção Clonal , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/efeitos dos fármacos , Humanos , Imunossupressores/uso terapêutico , Transplante de Órgãos/efeitos adversos , Fatores de Tempo , Tolerância ao Transplante/efeitos dos fármacos , Resultado do Tratamento
16.
Front Immunol ; 12: 661643, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093552

RESUMO

Despite advances in post-transplant management, the long-term survival rate of kidney grafts and patients has not improved as approximately forty percent of transplants fails within ten years after transplantation. Both immunologic and non-immunologic factors contribute to late allograft loss. Chronic kidney transplant rejection (CKTR) is often clinically silent yet progressive allogeneic immune process that leads to cumulative graft injury, deterioration of graft function. Chronic active T cell mediated rejection (TCMR) and chronic active antibody-mediated rejection (ABMR) are classified as two principal subtypes of CKTR. While significant improvements have been made towards a better understanding of cellular and molecular mechanisms and diagnostic classifications of CKTR, lack of early detection, differential diagnosis and effective therapies continue to pose major challenges for long-term management. Recent development of high throughput cellular and molecular biotechnologies has allowed rapid development of new biomarkers associated with chronic renal injury, which not only provide insight into pathogenesis of chronic rejection but also allow for early detection. In parallel, several novel therapeutic strategies have emerged which may hold great promise for improvement of long-term graft and patient survival. With a brief overview of current understanding of pathogenesis, standard diagnosis and challenges in the context of CKTR, this mini-review aims to provide updates and insights into the latest development of promising novel biomarkers for diagnosis and novel therapeutic interventions to prevent and treat CKTR.


Assuntos
Anticorpos/imunologia , Rejeição de Enxerto/imunologia , Transplante de Rim/métodos , Rim/imunologia , Linfócitos T/imunologia , Biomarcadores/análise , Doença Crônica , Diagnóstico Precoce , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/prevenção & controle , Humanos , Rim/patologia , Transplante de Rim/efeitos adversos , Transplante Homólogo
17.
PLoS One ; 16(6): e0252979, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34111211

RESUMO

BACKGROUND: Kidney transplant recipients are a unique cohort in regard to SARS-CoV 2 susceptibility and clinical course, owing to their immunosuppressed state and propensity for kidney injury. The primary purpose of this study is to ascertain if, in kidney transplant recipients, SARS-CoV 2 infection impacts long term renal allograft function. METHODS: This retrospective, single-center study reviewed 53 kidney transplant recipients with a positive SARS-CoV-2 PCR at NMH from January 1, 2020 to June 30, 2020. RESULTS: Change in eGFR from baseline kidney function prior to infection to 90 days after the first positive SARS-CoV 2 test was +1.76%, -17.5% and -23.16% the mild, moderate and severe disease groups respectively. There was a significant decline in kidney function in the moderate and severe disease cohorts as compared to the mild disease cohort, with respective p values of p = 0.0002 and p = 0.021. Relative to the mild disease cohort, the moderate and severe disease cohorts also demonstrated significantly increased risk of developing AKI (66%, 85%), both with p values of P = 0.0001. CONCLUSIONS: Clinically severe SARS-CoV 2 infection is associated with greater risk of acute kidney injury and greater decline in renal allograft function at 90 days post infection, compared to mild disease.


Assuntos
Injúria Renal Aguda/etiologia , Aloenxertos/virologia , COVID-19/complicações , Transplante de Rim , Rim/virologia , SARS-CoV-2/isolamento & purificação , Injúria Renal Aguda/fisiopatologia , Aloenxertos/fisiopatologia , COVID-19/diagnóstico , COVID-19/virologia , Humanos , Rim/fisiopatologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Transplantados
18.
J Heart Lung Transplant ; 40(6): 435-446, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33846079

RESUMO

Cardiac Allograft Vasculopathy (CAV) is a leading contributor to late transplant rejection. Although implicated, the mechanisms by which bone marrow-derived cells promote CAV remain unclear. Emerging evidence implicates the cell surface receptor tyrosine kinase AXL to be elevated in rejecting human allografts. AXL protein is found on multiple cell types, including bone marrow-derived myeloid cells. The causal role of AXL from this compartment and during transplant is largely unknown. This is important because AXL is a key regulator of myeloid inflammation. Utilizing experimental chimeras deficient in the bone marrow-derived Axl gene, we report that Axl antagonizes cardiac allograft survival and promotes CAV. Flow cytometric and histologic analyses of Axl-deficient transplant recipients revealed reductions in both allograft immune cell accumulation and vascular intimal thickness. Co-culture experiments designed to identify cell-intrinsic functions of Axl uncovered complementary cell-proliferative pathways by which Axl promotes CAV-associated inflammation. Specifically, Axl-deficient myeloid cells were less efficient at increasing the replication of both antigen-specific T cells and vascular smooth muscle cells (VSMCs), the latter a key hallmark of CAV. For the latter, we discovered that Axl-was required to amass the VSMC mitogen Platelet-Derived Growth Factor. Taken together, our studies reveal a new role for myeloid Axl in the progression of CAV and mitogenic crosstalk. Inhibition of AXL-protein, in combination with current standards of care, is a candidate strategy to prolong cardiac allograft survival.


Assuntos
Células da Medula Óssea/patologia , Regulação da Expressão Gênica , Rejeição de Enxerto/genética , Transplante de Coração/efeitos adversos , Músculo Liso Vascular/metabolismo , Miócitos Cardíacos/metabolismo , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/genética , Adulto , Animais , Células da Medula Óssea/metabolismo , Proliferação de Células , Células Cultivadas , Modelos Animais de Doenças , Ecocardiografia , Citometria de Fluxo , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/metabolismo , Sobrevivência de Enxerto , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Músculo Liso Vascular/patologia , Miócitos Cardíacos/patologia , Miócitos de Músculo Liso , Proteínas Proto-Oncogênicas/biossíntese , RNA/genética , Receptores Proteína Tirosina Quinases/biossíntese , Transplante Homólogo , Receptor Tirosina Quinase Axl
19.
J Clin Med ; 10(13)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34209541

RESUMO

The Food and Drug Administration (FDA) has been regulating human islets for allotransplantation as a biologic drug in the US. Consequently, the requirement of a biological license application (BLA) approval before clinical use of islet transplantation as a standard of care procedure has stalled the development of the field for the last 20 years. Herein, we provide our commentary to the multiple FDA's position papers and guidance for industry arguing that BLA requirement has been inappropriately applied to allogeneic islets, which was delivered to the FDA Cellular, Tissue and Gene Therapies Advisory Committee on 15 April 2021. We provided evidence that BLA requirement and drug related regulations are inadequate in reassuring islet product quality and potency as well as patient safety and clinical outcomes. As leaders in the field of transplantation and endocrinology under the "Islets for US Collaborative" designation, we examined the current regulatory status of islet transplantation in the US and identified several anticipated negative consequences of the BLA approval. In our commentary we also offer an alternative pathway for islet transplantation under the regulatory framework for organ transplantation, which would address deficiencies of in current system.

20.
Clin Transplant ; 24(2): 169-74, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20070317

RESUMO

BACKGROUND: The past decade has seen laparoscopic donor nephrectomy (LDN) transform into a standard of care procedure. Furthermore, LDN has evolved with the introduction of new technologies aimed at increasing efficiency and safety. There are few large, single center experiences detailing the results of LDN, its associated complications, and their management. METHODS: We performed a retrospective review of 1200 LDN performed at our center for both pediatric and adult recipients. RESULTS: Mean body mass index of donors was 27.1 (range 17-48). Twenty-six percent of kidneys had multiple renal arteries. Greater than 99% were left LDN. Mean length of stay was 1.37 +/- 0.6 d, which decreased to 1.1 +/- 0.5 d for the last 475 cases. The overall complication rate was 5.6%. Among those patients, 1.6% of the patients experienced an intraoperative complication, including eight renovascular injuries; 7/8 renovascular injuries led to open conversion. Four conversions were elective; our overall conversion rate was 0.92%; 4.0% had a post-operative complication; 1.2% required readmission for complication management. Three of 1200 patients have required reoperation for prolonged ileus and internal hernia (2), respectively. There have been no cases of donor renal failure or death. Since 2003, we have routinely used hand-assisted LDN (HALDN). There have been no cases of primary non-function. Urologic complications have been uncommon. CONCLUSIONS: Our series supports the safety and efficacy of LDN/HALDN.


Assuntos
Transplante de Rim/estatística & dados numéricos , Nefrectomia/métodos , Adulto , Índice de Massa Corporal , Função Retardada do Enxerto/epidemiologia , Feminino , Humanos , Complicações Intraoperatórias/epidemiologia , Laparoscopia/métodos , Tempo de Internação , Doadores Vivos , Pessoa de Meia-Idade , Nefrectomia/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Estudos Retrospectivos , Resultado do Tratamento
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