RESUMO
High frequencies of donor-reactive memory T cells in the periphery of transplant candidates prior to transplantation are linked to the development of posttransplant acute rejection episodes and reduced allograft function. Rabbit antithymocyte globulin (rATG) effectively depletes naïve CD4+ and CD8+ T cells for >6 months posttransplant, but rATG's effects on human donor-reactive T cells have not been carefully determined. To address this, we performed T cell receptor ß-chain sequencing on peripheral blood mononuclear cells aliquots collected pretransplant and serially posttransplant in 7 kidney transplant recipients who received rATG as induction therapy. We tracked the evolution of the donor-reactive CD4+ and CD8+ T cell repertoires and identified stimulated pretransplant, CTV-(surface dye)-labeled, peripheral blood mononuclear cells from each patient with donor cells or third-party cells. Our analyses showed that while rATG depleted CD4+ T cells in all tested subjects, a subset of donor-reactive CD8+ T cells that were present at high frequencies pretransplant, consistent with expanded memory cells, resisted rATG depletion, underwent posttransplant expansion and were functional. Together, our data support the conclusion that a subset of human memory CD8+ T cells specifically reactive to donor antigens expand in vivo despite induction therapy with rATG and thus have the potential to mediate allograft damage.
Assuntos
Soro Antilinfocitário , Linfócitos T CD8-Positivos , Rejeição de Enxerto , Transplante de Rim , Doadores de Tecidos , Transplante de Rim/efeitos adversos , Humanos , Soro Antilinfocitário/uso terapêutico , Linfócitos T CD8-Positivos/imunologia , Masculino , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/etiologia , Pessoa de Meia-Idade , Feminino , Adulto , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos de Linfócitos T/genética , Animais , Linfócitos T CD4-Positivos/imunologia , Prognóstico , Seguimentos , Falência Renal Crônica/cirurgia , Falência Renal Crônica/imunologia , Coelhos , Sobrevivência de Enxerto/imunologia , Depleção LinfocíticaRESUMO
Mouse models have been instrumental in understanding mechanisms of transplant rejection and tolerance, but cross-study reproducibility and translation of experimental findings into effective clinical therapies are issues of concern. The Mouse Models in Transplantation symposium gathered scientists and physician-scientists involved in basic and clinical research in transplantation to discuss the strengths and limitations of mouse transplant models and strategies to enhance their utility. Participants recognized that increased procedure standardization, including the use of prespecified, defined endpoints, and statistical power analyses, would benefit the field. They also discussed the generation of new models that incorporate environmental and genetic variables affecting clinical outcomes as potentially important. If implemented, these strategies are expected to improve the reproducibility of mouse studies and increase their translation to clinical trials and, ideally, new Food and Drug Administration-approved drugs.
Assuntos
Modelos Animais de Doenças , Animais , Camundongos , Humanos , Rejeição de Enxerto/prevenção & controle , Rejeição de Enxerto/etiologia , Transplante de Órgãos , Modelos Animais , Reprodutibilidade dos Testes , Transplante/métodosRESUMO
Microglia, the brain's resident macrophages, maintain brain homeostasis and respond to injury and infection. During aging they undergo functional changes, but the underlying mechanisms and their contributions to neuroprotection versus neurodegeneration are unclear. Previous studies suggested that microglia are sex dimorphic, so we compared microglial aging in mice of both sexes. RNA-sequencing of hippocampal microglia revealed more aging-associated changes in female microglia than male microglia, and more sex differences in old microglia than young microglia. Pathway analyses and subsequent validation assays revealed a stronger AKT-mTOR-HIF1α-driven shift to glycolysis among old female microglia and indicated that C3a production and detection was elevated in old microglia, especially in females. Recombinant C3a induced AKT-mTOR-HIF1α signaling and increased the glycolytic and phagocytic activity of young microglia. Single cell analyses attributed the aging-associated sex dimorphism to more abundant disease-associated microglia (DAM) in old female mice than old male mice, and evaluation of an Alzheimer's Disease mouse model revealed that the metabolic and complement changes are also apparent in the context of neurodegenerative disease and are strongest in the neuroprotective DAM2 subset. Collectively, our data implicate autocrine C3a-C3aR signaling in metabolic reprogramming of microglia to neuroprotective DAM during aging, especially in females, and also in Alzheimer's Disease.
Assuntos
Envelhecimento , Microglia , Caracteres Sexuais , Animais , Microglia/metabolismo , Feminino , Camundongos , Envelhecimento/metabolismo , Envelhecimento/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/genética , Transdução de Sinais/fisiologiaRESUMO
BACKGROUND: Kidney transplant recipients (KTRs) generate lower antibody responses to messenger RNA (mRNA)-based severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination, yet precise mechanisms for this poor response remain uncertain. One potential contributor is suboptimal spike antigen (sAg) translation and expression owing to transplant immunosuppression, which might lead to insufficient exposure to develop humoral and/or cellular immune responses. METHODS: Within a single-arm clinical trial, 65 KTRs underwent ultrasensitive plasma sAg testing before, and 3 and 14 days after, the third mRNA vaccine doses. Anti-SARS-CoV-2 spike antibodies (anti-receptor binding domain [anti-RBD]) were serially measured at 14 and 30 days post-vaccination. Associations between sAg detection and clinical factors were assessed. Day 30 anti-RBD titer was compared among those with versus without sAg expression using Wilcoxon rank sum testing. RESULTS: Overall, 16 (25%) KTRs were sAg positive (sAg+) after vaccination, peaking at day 3. Clinical and laboratory factors were broadly similar in sAg(+) versus sAg(-) KTRs. sAg(+) status was significantly negatively associated with day 30 anti-RBD response, with median (interquartile range) 10.8 (<0.4-338.3) U/mL if sAg(+) versus 709 (10.5-2309.5) U/mL if sAg(-) (i.e., 66-fold lower; p = .01). CONCLUSION: Inadequate plasma sAg does not likely drive poor antibody responses in KTRs, rather sAg detection implies insufficient immune response to rapidly clear vaccine antigen from blood. Other downstream mechanisms such as sAg trafficking and presentation should be explored.
Assuntos
Anticorpos Antivirais , Vacinas contra COVID-19 , COVID-19 , Transplante de Rim , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Transplantados , Humanos , Transplante de Rim/efeitos adversos , Glicoproteína da Espícula de Coronavírus/imunologia , Masculino , Feminino , Pessoa de Meia-Idade , Anticorpos Antivirais/sangue , SARS-CoV-2/imunologia , COVID-19/prevenção & controle , COVID-19/imunologia , COVID-19/sangue , Vacinas contra COVID-19/imunologia , Adulto , Idoso , Formação de Anticorpos , Vacinação , Vacina BNT162/imunologiaRESUMO
Transplantation is the ideal therapy for end-stage organ failure, but outcomes for all transplant organs are suboptimal, underscoring the need to develop novel approaches to improve graft survival and function. The complement system, traditionally considered a component of innate immunity, is now known to broadly control inflammation and crucially contribute to induction and function of adaptive T-cell and B-cell immune responses, including those induced by alloantigens. Interest of pharmaceutical industries in complement therapeutics for nontransplant indications and the understanding that the complement system contributes to solid organ transplantation injury through multiple mechanisms raise the possibility that targeting specific complement components could improve transplant outcomes and patient health. Here, we provide an overview of complement biology and review the roles and mechanisms through which the complement system is pathogenically linked to solid organ transplant injury. We then discuss how this knowledge has been translated into novel therapeutic strategies to improve organ transplant outcomes and identify areas for future investigation. Although the clinical application of complement-targeted therapies in transplantation remains in its infancy, the increasing availability of new agents in this arena provides a rich environment for potentially transformative translational transplant research.
Assuntos
Inativadores do Complemento , Proteínas do Sistema Complemento , Rejeição de Enxerto , Sobrevivência de Enxerto , Transplante de Órgãos , Humanos , Proteínas do Sistema Complemento/imunologia , Transplante de Órgãos/efeitos adversos , Sobrevivência de Enxerto/efeitos dos fármacos , Sobrevivência de Enxerto/imunologia , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Animais , Inativadores do Complemento/uso terapêutico , Ativação do Complemento/efeitos dos fármacos , Resultado do TratamentoRESUMO
Antibody-mediated rejection (AMR), including chronic AMR (cAMR), causes ~50% of kidney allograft losses each year. Despite attempts to develop well-tolerated and effective therapeutics for the management of AMR, to date, none has obtained FDA approval, thereby highlighting an urgent unmet medical need. Discoveries over the past decade from basic, translational and clinical studies of transplant recipients have provided a foundation for developing novel therapeutic approaches to preventing and treating AMR and cAMR. These interventions are aimed at reducing donor-specific antibody levels, decreasing graft injury and fibrosis, and preserving kidney function. Innovative approaches emerging from basic science findings include targeting interactions between alloreactive T cells and B cells, and depleting alloreactive memory B cells, as well as donor-specific antibody-producing plasmablasts and plasma cells. Therapies aimed at reducing the cytotoxic antibody effector functions mediated by natural killer cells and the complement system, and their associated pro-inflammatory cytokines, are also undergoing evaluation. The complexity of the pathogenesis of AMR and cAMR suggest that multiple approaches will probably be required to treat these disease processes effectively. Definitive answers await results from large, double-blind, multicentre, randomized controlled clinical trials.
Assuntos
Transplante de Rim , Humanos , Rejeição de Enxerto/prevenção & controle , Rejeição de Enxerto/tratamento farmacológico , Transplante Homólogo , Imunoglobulinas , Aloenxertos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Virus-induced memory T cells often express functional cross-reactivity, or heterologous immunity, to other viruses and to allogeneic MHC molecules that is an important component of pathogenic responses to allogeneic transplants. During immune responses, antigen-reactive naive and central memory T cells proliferate in secondary lymphoid organs to achieve sufficient cell numbers to effectively respond, whereas effector memory T cell proliferation occurs directly within the peripheral inflammatory microenvironment. Mechanisms driving heterologous memory T cell proliferation and effector function expression within peripheral tissues remain poorly understood. Here, we dissected proliferation of heterologous donor-reactive memory CD8+ T cells and their effector functions following infiltration into heart allografts with low or high intensities of ischemic inflammation. Proliferation within both ischemic conditions required p40 homodimer-induced IL-15 transpresentation by graft DCs, but expression of effector functions mediating acute allograft injury occurred only in high-ischemic allografts. Transcriptional responses of heterologous donor-reactive memory CD8+ T cells were distinct from donor antigen-primed memory CD8+ T cells during early activation in allografts and at graft rejection. Overall, the results provide insights into mechanisms driving heterologous effector memory CD8+ T cell proliferation and the separation between proliferation and effector function that is dependent on the intensity of inflammation within the tissue microenvironment.