RESUMO
Surgical trauma and ischemia reperfusion injury (IRI) are unavoidable aspects of any solid organ transplant procedure. They trigger a multifactorial antigen-independent inflammatory process that profoundly affects both the early and long-term outcomes of the transplanted organ. The injury associated with donor organ procurement, storage, and engraftment triggers innate immune activation that inevitably results in cell death, which may occur in many different forms. Dying cells in donor grafts release damage-associated molecular patterns (DAMPs), which alert recipient innate cells, including macrophages and dendritic cells (DCs), through the activation of the complement cascade and toll-like receptors (TLRs). The long-term effect of inflammation on innate immune cells is associated with changes in cellular metabolism that skew the cells towards aerobic glycolysis, resulting in innate immune cell activation and inflammatory cytokine production. The different roles of proinflammatory cytokines in innate immune activation have been described, and these cytokines also stimulate optimal T-cell expansion during allograft rejection. Therefore, early innate immune events after organ transplantation determine the fate of the adaptive immune response. In this review, we summarize the contributions of innate immunity to allograft rejection and discuss recent studies and emerging concepts in the targeted delivery of therapeutics to modulate the innate immune system to enhance allograft survival.
Assuntos
Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/imunologia , Imunidade Inata/fisiologia , Inflamação/imunologia , Transplante de Órgãos/efeitos adversos , Traumatismo por Reperfusão/imunologia , Transplante Homólogo , Animais , Morte Celular/imunologia , Proteínas do Sistema Complemento/imunologia , Proteínas do Sistema Complemento/metabolismo , Células Dendríticas/imunologia , Rejeição de Enxerto/terapia , Humanos , Inflamação/metabolismo , Macrófagos/imunologia , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/terapia , Transdução de Sinais/imunologia , Linfócitos T/imunologia , Receptores Toll-Like/imunologia , Receptores Toll-Like/metabolismoRESUMO
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.
Assuntos
Sobrevivência de Enxerto/imunologia , Terapia de Imunossupressão , Inflamação/imunologia , Células Mieloides/imunologia , Células Mieloides/metabolismo , Transplante de Órgãos , Aloenxertos , Animais , Biomarcadores , Proteína HMGB1/genética , Tolerância Imunológica , Imunidade Inata , Memória Imunológica , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Serina-Treonina Quinases TOR/metabolismo , Vimentina/genéticaRESUMO
The colony-stimulating factor 1 (CSF1) regulates the differentiation and function of tissue macrophages and determines the outcome of the immune response. The molecular mechanisms behind CSF1-mediated macrophage development remain to be elucidated. Here we demonstrate that neutrophil-derived CSF1 controls macrophage polarization and proliferation, which is necessary for the induction of tolerance. Inhibiting neutrophil production of CSF1 or preventing macrophage proliferation, using targeted nanoparticles loaded with the cell cycle inhibitor simvastatin, abrogates the induction of tolerance. These results provide new mechanistic insights into the developmental requirements of tolerogenic macrophages and identify CSF1 producing neutrophils as critical regulators of the immunological response.
Assuntos
Transplante de Coração , Tolerância Imunológica/imunologia , Fator Estimulador de Colônias de Macrófagos/metabolismo , Macrófagos/imunologia , Neutrófilos/imunologia , Tolerância ao Transplante/imunologia , Animais , Diferenciação Celular , Proliferação de Células , Feminino , Humanos , Macrófagos/citologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Neutrófilos/metabolismo , Transdução de SinaisRESUMO
Tissue effector cells of the monocyte lineage can differentiate into different cell types with specific cell function depending on their environment. The phenotype, developmental requirements, and functional mechanisms of immune protective macrophages that mediate the induction of transplantation tolerance remain elusive. Here, we demonstrate that costimulatory blockade favored accumulation of DC-SIGN-expressing macrophages that inhibited CD8(+) T cell immunity and promoted CD4(+)Foxp3(+) Treg cell expansion in numbers. Mechanistically, that simultaneous DC-SIGN engagement by fucosylated ligands and TLR4 signaling was required for production of immunoregulatory IL-10 associated with prolonged allograft survival. Deletion of DC-SIGN-expressing macrophages in vivo, interfering with their CSF1-dependent development, or preventing the DC-SIGN signaling pathway abrogated tolerance. Together, the results provide new insights into the tolerogenic effects of costimulatory blockade and identify DC-SIGN(+) suppressive macrophages as crucial mediators of immunological tolerance with the concomitant therapeutic implications in the clinic.
Assuntos
Moléculas de Adesão Celular/metabolismo , Rejeição de Enxerto/prevenção & controle , Transplante de Coração , Lectinas Tipo C/metabolismo , Macrófagos/imunologia , Receptores de Superfície Celular/metabolismo , Linfócitos T Reguladores/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Moléculas de Adesão Celular/genética , Células Cultivadas , Fatores de Transcrição Forkhead/metabolismo , Rejeição de Enxerto/etiologia , Tolerância Imunológica , Interleucina-10/metabolismo , Lectinas Tipo C/genética , Fator Estimulador de Colônias de Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Terapia de Alvo Molecular , Receptores de Superfície Celular/genética , Transdução de Sinais , Receptor 4 Toll-Like/metabolismo , Tolerância ao Transplante , Regulação para CimaRESUMO
Myeloid derived suppressor cells (MDSC) contribute to the negative regulation of immune response in cancer patients. This review summarizes results on important issues related to MDSC biology, including expansion and activation of MDSC, phenotype, and subsets as well pathways and different mechanisms by which these cells exert their suppressive effect. Recent observations suggesting that MDSC may have roles in transplant tolerance are presented. Although therapeutic targeting and destruction of MDCS is of primary interest in cancer patients, in transplantation it will instead be necessary to induce, expand, and activate these cells; thus current possibilities for in vitro generation of MDSC are also discussed.
Assuntos
Rejeição de Enxerto/imunologia , Imunoterapia , Células Mieloides/metabolismo , Neoplasias/imunologia , Tolerância ao Transplante , Animais , Rejeição de Enxerto/terapia , Humanos , Tolerância Imunológica , Imunidade Celular , Células Mieloides/patologia , Neoplasias/patologia , Neoplasias/terapia , Transplante de Órgãos , Tolerância ao Transplante/imunologia , Evasão TumoralRESUMO
PURPOSE OF REVIEW: Understanding the interplay between myeloid dendritic cells and T cells under tolerogenic conditions, and whether their interactions induce the development of antigen-specific regulatory T cells (Tregs) is critical to uncover the mechanisms involved in the induction of indefinite allograft survival. RECENT FINDINGS: Myeloid dendritic cell-T-cell interactions are seminal events that determine the outcome of the immune response, and multiple in-vitro protocols suggest the generation of tolerogenic myeloid dendritic cells that modulate T-cell responses, and determine the outcome of the immune response to an allograft following adoptive transfer. We believe that identifying specific conditions that lead to the generation of tolerogenic myeloid dendritic cells and Tregs are critical for the manipulation of the immune response towards the development of transplantation tolerance. SUMMARY: We summarize recent findings regarding specific culture conditions that generate tolerogenic myeloid dendritic cells that induce T-cell hyporesponsiveness and Treg development, which represents a novel immunotherapeutic approach to promote the induction of indefinite graft survival prolongation. The interpretations presented here illustrate that different mechanisms govern the generation of tolerogenic myeloid dendritic cells, and we discuss the concomitant therapeutic implications.
Assuntos
Células Dendríticas/transplante , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto , Imunoterapia/métodos , Células Mieloides/transplante , Linfócitos T Reguladores/imunologia , Tolerância ao Transplante , Animais , Técnicas de Cultura de Células , Células Cultivadas , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Rejeição de Enxerto/imunologia , Humanos , Células Mieloides/imunologiaRESUMO
One of the main unresolved questions in solid organ transplantation is how to establish indefinite graft survival that is free from long-term treatment with immunosuppressive drugs and chronic rejection (i.e., the establishment of tolerance). The failure to achieve this goal may be related to the difficulty in identifying the phenotype and function of the cell subsets that participate in the induction of tolerance. To address this issue, we investigated the suppressive roles of recipient myeloid cells that may be manipulated to induce tolerance to transplanted hearts in mice. Using depleting mAbs, clodronate-loaded liposomes, and transgenic mice specific for depletion of CD11c+, CD11b+, or CD115+ cells, we identified a tolerogenic role for CD11b+CD115+Gr1+ monocytes during the induction of tolerance by costimulatory blockade with CD40L-specific mAb. Early after transplantation, Gr1+ monocytes migrated from the bone marrow into the transplanted organ, where they prevented the initiation of adaptive immune responses that lead to allograft rejection and participated in the development of Tregs. Our results suggest that mobilization of bone marrow CD11b+CD115+Gr1+ monocytes under sterile inflammatory conditions mediates the induction of indefinite allograft survival. We propose that manipulating the common bone marrow monocyte progenitor could be a useful clinical therapeutic approach for inducing transplantation tolerance.
Assuntos
Tolerância ao Transplante/efeitos dos fármacos , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacologia , Medula Óssea/efeitos dos fármacos , Medula Óssea/imunologia , Ligante de CD40/imunologia , Sobrevivência de Enxerto/efeitos dos fármacos , Sobrevivência de Enxerto/imunologia , Sobrevivência de Enxerto/fisiologia , Tolerância Imunológica/efeitos dos fármacos , Tolerância Imunológica/imunologia , Interleucina-2/imunologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Tolerância ao Transplante/imunologiaRESUMO
Rodent models of solid organ transplantation have been used for many decades. Standardized operative techniques resulting in highly reproducible survival rates have been developed for several organs. This allowed scientists to investigate many clinically relevant problems, test new drugs and establish novel treatment regimens. Recently, many studies used these models to explore novel issues such as graft modification by pharmaceutical, surgical or genetic engineering methods, post-transplant regeneration, leukocyte trafficking or interactions between the innate and allo-specific arms of the immune response. The results from these studies clearly facilitate a more complex and comprehensive understanding of existing problem. The long-established methods of rodent organ transplantation, combined with the newest achievements in surgical techniques, biotechnology and imaging, will remain indispensable tools of transplantation biology.
Assuntos
Transplante de Órgãos/métodos , Animais , Movimento Celular , Transplante de Tecido Fetal , Engenharia Genética , Terapia Genética , Imunidade Inata , Precondicionamento Isquêmico , Leucócitos/fisiologia , Camundongos , Modelos Animais , Soluções para Preservação de Órgãos , Ratos , RegeneraçãoRESUMO
Presence of preformed lymphocytotoxic antibodies may represent a barrier to isolated intestinal transplantation (IITx). We developed an intravenous immunoglobulins (IVIg) based desensitization protocol for candidates with high panel-reactive antibodies (PRA). Six patients with a mean PRA of 72+/-22% were included in a four-level (L) protocol with escalating doses of IVIg (L1, L2), addition of mycophenolate mofetil (MMF) or plasmapheresis (L3); and anti-CD20 (Rituximab) (L4). Four of six candidates improved their PRAs (from a mean of 66.2% to 25.5%; P=0.01) and were successfully transplanted. At a mean follow-up of 8 months, number and severity of rejection episodes of protocol patients did not differ from patients with low PRA transplanted during the same period. These data support the use of IVIg to desensitize patients waiting for IITx. It increases the applicability of IITx, and reduces the waiting time and mortality on the waiting list with outcomes comparable to nonsensitized recipients.
Assuntos
Imunoglobulinas Intravenosas/farmacologia , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/transplante , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Humanos , Imunoglobulinas Intravenosas/imunologia , Fatores Imunológicos/imunologia , Fatores Imunológicos/farmacologia , Intestino Delgado/imunologia , Pessoa de Meia-Idade , Condicionamento Pré-TransplanteRESUMO
BACKGROUND: Intestinal transplantation has been hampered by high rates of intestinal allograft rejection. One mechanism of altering rejection in other organ transplant models has been blockade of second set T-cell costimulatory signals. AH.F5, a novel hamster anti-rat monoclonal antibody to CD154, blocks CD40-dependent T-cell costimulation. We hypothesized that blockade of this pathway might abrogate rejection in a rodent orthotopic survival model of intestinal transplantation. METHODS: Eight groups were studied with different dosing schema, including syngeneic transplants (group 1), untreated allogeneic transplants (group 2), allogeneic transplants plus multiple doses of AH.F5 alone given IV or s.c. (groups 3 and 4), allogeneic transplants plus donor splenocyte preconditioning with and without single dose AH.F5 (groups 5 and 6), and donor splenocyte preconditioning followed by multiple doses of AH.F5 with and without thymectomy (groups 7 and 8). RESULTS: Control animals all died within 12 days of transplantation, whereas antibody-alone and splenocytes-alone resulted in modest prolongation of survival to 16 days. Only animals treated with splenocytes before transplantation and AH.F5 survived long-term (>60 days, group 8). These animals tolerated donor-specific skin grafts, rejected third-party grafts, and fed normally. However, their weight gain was subnormal and they demonstrated intestinal muscular thickening, which might represent chronic rejection. Thymectomy prevented the induction of tolerance. CONCLUSIONS: AH.F5 prevents acute intestinal allograft rejection in combination with donor-specific splenocyte preconditioning. We achieved long-term survival and the animals appeared tolerant. Central conditioning is essential for success with this antibody when used alone. Further studies with different dosing regimens or second agents seem warranted.