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1.
Nat Immunol ; 16(8): 819-828, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26147686

RESUMO

Fat-associated lymphoid clusters (FALCs) are a type of lymphoid tissue associated with visceral fat. Here we found that the distribution of FALCs was heterogeneous, with the pericardium containing large numbers of these clusters. FALCs contributed to the retention of B-1 cells in the peritoneal cavity through high expression of the chemokine CXCL13, and they supported B cell proliferation and germinal center differentiation during peritoneal immunological challenges. FALC formation was induced by inflammation, which triggered the recruitment of myeloid cells that expressed tumor-necrosis factor (TNF) necessary for signaling via the TNF receptors in stromal cells. Natural killer T cells (NKT cells) restricted by the antigen-presenting molecule CD1d were likewise required for the inducible formation of FALCs. Thus, FALCs supported and coordinated the activation of innate B cells and T cells during serosal immune responses.


Assuntos
Inflamação/imunologia , Gordura Intra-Abdominal/imunologia , Linfócitos/imunologia , Tecido Linfoide/imunologia , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Quimiocina CXCL13/genética , Quimiocina CXCL13/imunologia , Quimiocina CXCL13/metabolismo , Citometria de Fluxo , Expressão Gênica/imunologia , Inflamação/genética , Inflamação/metabolismo , Gordura Intra-Abdominal/metabolismo , Linfócitos/metabolismo , Tecido Linfoide/citologia , Tecido Linfoide/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Microscopia Confocal , Células Mieloides/imunologia , Células Mieloides/metabolismo , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/metabolismo , Receptores do Fator de Necrose Tumoral/genética , Receptores do Fator de Necrose Tumoral/imunologia , Receptores do Fator de Necrose Tumoral/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Estromais/imunologia , Células Estromais/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo
2.
J Immunol ; 199(3): 974-981, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28646041

RESUMO

Although strategies that block FOXP3-dependent regulatory T cell function (CTLA4 blockade) and the inhibitory receptor PD1 have shown great promise in promoting antitumor immune responses in humans, their widespread implementation for cancer immunotherapy has been hampered by significant off-target autoimmune side effects that can be lethal. Our work has shown that absence of OX40 and CD30 costimulatory signals prevents CD4 T cell-driven autoimmunity in Foxp3-deficient mice, suggesting a novel way to block these side effects. In this study, we show that excellent antitumor CD8 T cell responses can be achieved in Foxp3KO mice deficient in OX40 and CD30 signals, particularly in the presence of concurrent PD1 blockade. Furthermore, excellent antitumor immune responses can also be achieved using combinations of Abs that block CTLA4, PD1, OX40, and CD30 ligands, without CD4 T cell-driven autoimmunity. By dissociating autoimmune side effects from anticancer immune responses, this potentially shifts this antitumor approach to patients with far less advanced disease.


Assuntos
Autoimunidade , Ligante CD30/antagonistas & inibidores , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptores OX40/antagonistas & inibidores , Animais , Ligante CD30/imunologia , Antígeno CTLA-4/imunologia , Fatores de Transcrição Forkhead/deficiência , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Imunoterapia , Ligantes , Ativação Linfocitária , Camundongos , Camundongos Knockout , Neoplasias/terapia , Receptor de Morte Celular Programada 1/imunologia , Receptores OX40/imunologia , Linfócitos T Reguladores/imunologia
3.
J Immunol ; 192(6): 2659-66, 2014 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-24510964

RESUMO

In the thymus, interactions with both cortical and medullary microenvironments regulate the development of self-tolerant conventional CD4(+) and CD8(+) αßT cells expressing a wide range of αßTCR specificities. Additionally, the cortex is also required for the development of invariant NKT (iNKT) cells, a specialized subset of T cells that expresses a restricted αßTCR repertoire and is linked to the regulation of innate and adaptive immune responses. Although the role of the cortex in this process is to enable recognition of CD1d molecules expressed by CD4(+)CD8(+) thymocyte precursors, the requirements for additional thymus microenvironments during iNKT cell development are unknown. In this study, we reveal a role for medullary thymic epithelial cells (mTECs) during iNKT cell development in the mouse thymus. This requirement for mTECs correlates with their expression of genes required for IL-15 trans-presentation, and we show that soluble IL-15/IL-15Rα complexes restore iNKT cell development in the absence of mTECs. Furthermore, mTEC development is abnormal in iNKT cell-deficient mice, and early stages in iNKT cell development trigger receptor activator for NF-κB ligand-mediated mTEC development. Collectively, our findings demonstrate that intrathymic iNKT cell development requires stepwise interactions with both the cortex and the medulla, emphasizing the importance of thymus compartmentalization in the generation of both diverse and invariant αßT cells. Moreover, the identification of a novel requirement for iNKT cells in thymus medulla development further highlights the role of both innate and adaptive immune cells in thymus medulla formation.


Assuntos
Diferenciação Celular/imunologia , Microambiente Celular/imunologia , Células Epiteliais/imunologia , Células T Matadoras Naturais/imunologia , Animais , Antígenos CD1d/genética , Antígenos CD1d/imunologia , Antígenos CD1d/metabolismo , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Microambiente Celular/efeitos dos fármacos , Microambiente Celular/genética , Células Epiteliais/metabolismo , Células Epiteliais/transplante , Citometria de Fluxo , Interleucina-15/administração & dosagem , Interleucina-15/genética , Interleucina-15/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células T Matadoras Naturais/metabolismo , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Ligante RANK/imunologia , Ligante RANK/metabolismo , Receptor Ativador de Fator Nuclear kappa-B/imunologia , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Receptores de Interleucina-15/administração & dosagem , Receptores de Interleucina-15/genética , Receptores de Interleucina-15/imunologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Timócitos/citologia , Timócitos/imunologia , Timócitos/metabolismo , Timo/citologia , Timo/imunologia , Timo/metabolismo , Fator de Transcrição RelB/genética , Fator de Transcrição RelB/imunologia , Fator de Transcrição RelB/metabolismo
4.
Eur J Immunol ; 44(8): 2318-30, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24825601

RESUMO

The generation of immune cells from BM precursors is a carefully regulated process. This is essential to limit the potential for oncogenesis and autoimmunity yet protect against infection. How infection modulates this is unclear. Salmonella can colonize systemic sites including the BM and spleen. This resolving infection has multiple IFN-γ-mediated acute and chronic effects on BM progenitors, and during the first week of infection IFN-γ is produced by myeloid, NK, NKT, CD4(+) T cells, and some lineage-negative cells. After infection, the phenotype of BM progenitors rapidly but reversibly alters, with a peak ∼ 30-fold increase in Sca-1(hi) progenitors and a corresponding loss of Sca-1(lo/int) subsets. Most strikingly, the capacity of donor Sca-1(hi) cells to reconstitute an irradiated host is reduced; the longer donor mice are exposed to infection, and Sca-1(hi) c-kit(int) cells have an increased potential to generate B1a-like cells. Thus, Salmonella can have a prolonged influence on BM progenitor functionality not directly related to bacterial persistence. These results reflect changes observed in leucopoiesis during aging and suggest that BM functionality can be modulated by life-long, periodic exposure to infection. Better understanding of this process could offer novel therapeutic opportunities to modulate BM functionality and promote healthy aging.


Assuntos
Células da Medula Óssea/imunologia , Salmonelose Animal/imunologia , Células-Tronco/imunologia , Animais , Antígenos Ly/imunologia , Células da Medula Óssea/microbiologia , Células da Medula Óssea/patologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/microbiologia , Homeostase/imunologia , Interferon gama/imunologia , Proteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Salmonella/imunologia , Salmonelose Animal/patologia , Células-Tronco/microbiologia , Células-Tronco/patologia
5.
J Immunol ; 191(3): 1465-75, 2013 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-23817421

RESUMO

OX40 is a member of the TNFR superfamily that has potent costimulatory properties. Although the impact of blockade of the OX40-OX40 ligand (OX40L) pathway has been well documented in models of autoimmune disease, its effect on the rejection of allografts is less well defined. In this article, we show that the alloantigen-mediated activation of naive and memory CD4(+) T cells results in the induction of OX40 expression and that blockade of OX40-OX40L interactions prevents skin allograft rejection mediated by either subset of T cells. Moreover, a blocking anti-OX40 had no effect on the activation and proliferation of T cells; rather, effector T cells failed to accumulate in peripheral lymph nodes and subsequently migrate to skin allografts. This was found to be the result of an enhanced degree of cell death among proliferating effector cells. In clear contrast, blockade of OX40-OX40L interactions at the time of exposure to alloantigen enhanced the ability of regulatory T cells to suppress T cell responses to alloantigen by supporting, rather than diminishing, regulatory T cell survival. These data show that OX40-OX40L signaling contributes to the evolution of the adaptive immune response to an allograft via the differential control of alloreactive effector and regulatory T cell survival. Moreover, these data serve to further highlight OX40 and OX40L as therapeutic targets to assist the induction of tolerance to allografts and self-Ags.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Isoantígenos/imunologia , Glicoproteínas de Membrana/metabolismo , Receptores OX40/metabolismo , Linfócitos T Reguladores/imunologia , Fatores de Necrose Tumoral/metabolismo , Imunidade Adaptativa/imunologia , Animais , Linfócitos T CD4-Positivos/metabolismo , Movimento Celular , Proliferação de Células , Proteínas de Homeodomínio/genética , Tolerância Imunológica , Memória Imunológica , Ativação Linfocitária/imunologia , Glicoproteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Knockout , Ligante OX40 , Receptores OX40/imunologia , Transdução de Sinais/imunologia , Transplante de Pele/imunologia , Transplante Homólogo/imunologia , Fatores de Necrose Tumoral/imunologia
6.
Immunol Rev ; 241(1): 119-32, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21488894

RESUMO

Exposure to alloantigen in vivo or in vitro induces alloantigen reactive regulatory T cells that can control transplant rejection. The mechanisms that underpin the activity of alloantigen reactive regulatory T cells in vivo are common with those of regulatory T cells that prevent autoimmunity. The identification and characterization of regulatory T cells that control rejection and contribute to the induction of immunologic unresponsiveness to alloantigens in vivo has opened up exciting opportunities for new therapies in transplantation. Findings from laboratory studies are informing the design of clinical protocols using regulatory T cells as a cellular therapy.


Assuntos
Rejeição de Enxerto/terapia , Tolerância Imunológica , Imunoterapia Adotiva , Isoantígenos/imunologia , Linfócitos T Reguladores/imunologia , Animais , Autoimunidade , Protocolos Clínicos , Rejeição de Enxerto/imunologia , Humanos , Transplante de Órgãos , Linfócitos T Reguladores/transplante
7.
Curr Opin Organ Transplant ; 20(4): 385-91, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26107971

RESUMO

PURPOSE OF REVIEW: The purpose of this article is to review recent advances in our understanding of innate lymphoid cell function and to speculate on how these cells may become activated and influence the immune response to allogeneic tissues and cells following transplantation. RECENT FINDINGS: Innate lymphoid cells encompass several novel cell types whose wide-ranging roles in the immune system are only now being uncovered. Through cytokine production, cross-talk with both haematopoietic and nonhaematopoietic populations and antigen presentation to T cells, these cells have been shown to be key regulators in maintaining tissue integrity, as well as initiating and then sustaining immune responses. SUMMARY: It is now clear that innate lymphoid cells markedly contribute to immune responses and tissue repair in a number of disease contexts. Although experimental and clinical data on the behaviour of these cells following transplantation are scant, it is highly likely that innate lymphoid cells will perform similar functions in the alloimmune response following transplantation and therefore may be potential therapeutic targets for manipulation to prevent allograft rejection.


Assuntos
Imunidade Inata , Linfócitos/imunologia , Adaptação Fisiológica , Aloenxertos , Reações Cruzadas , Rejeição de Enxerto/imunologia , Humanos
8.
J Immunol ; 188(10): 4885-96, 2012 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-22490863

RESUMO

The cosignaling network mediated by the herpesvirus entry mediator (HVEM; TNFRSF14) functions as a dual directional system that involves proinflammatory ligand, lymphotoxin that exhibits inducible expression and competes with HSV glycoprotein D for HVEM, a receptor expressed by T lymphocytes (LIGHT; TNFSF14), and the inhibitory Ig family member B and T lymphocyte attenuator (BTLA). To dissect the differential contributions of HVEM/BTLA and HVEM/LIGHT interactions, topographically-specific, competitive, and nonblocking anti-HVEM Abs that inhibit BTLA binding, but not LIGHT, were developed. We demonstrate that a BTLA-specific competitor attenuated the course of acute graft-versus-host reaction in a murine F(1) transfer semiallogeneic model. Selective HVEM/BTLA blockade did not inhibit donor T cell infiltration into graft-versus-host reaction target organs, but decreased the functional activity of the alloreactive T cells. These results highlight the critical role of HVEM/BTLA pathway in the control of the allogeneic immune response and identify a new therapeutic target for transplantation and autoimmune diseases.


Assuntos
Reação Enxerto-Hospedeiro/imunologia , Receptores Imunológicos/antagonistas & inibidores , Membro 14 de Receptores do Fator de Necrose Tumoral/antagonistas & inibidores , Transdução de Sinais/imunologia , Transferência Adotiva , Animais , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/transplante , Células CHO , Movimento Celular/genética , Movimento Celular/imunologia , Cricetinae , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Ratos , Ratos Endogâmicos Lew , Receptores Imunológicos/fisiologia , Membro 14 de Receptores do Fator de Necrose Tumoral/administração & dosagem , Membro 14 de Receptores do Fator de Necrose Tumoral/genética , Proteínas Recombinantes de Fusão/administração & dosagem , Baço/citologia , Baço/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/transplante
9.
Eur J Immunol ; 40(11): 3107-16, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20865790

RESUMO

Accumulating evidence suggests that alloreactive memory T cells (Tm) may form a barrier to tolerance induction in large animals and humans due in part to a resistance to suppression by Treg. However, why Tm are resistant to regulation and how the Tm response to an allograft differs from that of naïve T cells, which are amenable to suppression by Treg, remains unknown. Here, we show that accelerated graft rejection mediated by CD8(+) Tm was due to the enhanced recruitment of PMN to allografts in a mouse skin allograft model. Importantly, depletion of PMN slowed the kinetics of (but did not prevent) rejection mediated by Tm and created a window of opportunity that allowed subsequent suppression of rejection by Treg. Taken together, we conclude that CD8(+) Tm are not intrinsically resistant to suppression by Treg but may rapidly inflict substantial graft damage before the establishment of regulatory mechanisms. These data suggest that if Tm responses can be attenuated transiently following transplantation, Treg may be able to maintain tolerance through the suppression of both memory and naïve alloreactive T-cell responses in the long term.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Rejeição de Enxerto/imunologia , Memória Imunológica , Transplante de Pele , Linfócitos T Reguladores/imunologia , Animais , Linfócitos T CD8-Positivos/patologia , Rejeição de Enxerto/genética , Rejeição de Enxerto/patologia , Procedimentos de Redução de Leucócitos , Camundongos , Camundongos Knockout , Neutrófilos/imunologia , Neutrófilos/patologia , Linfócitos T Reguladores/patologia , Transplante Homólogo
10.
Proc Natl Acad Sci U S A ; 104(50): 19954-9, 2007 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-18042727

RESUMO

Alloreactive memory T cells may be refractory to many of the tolerance-inducing strategies that are effective against naive T cells and thus present a significant barrier to long-term allograft survival. Because CD4(+)CD25(+) regulatory T cells (Tregs) are critical elements of many approaches to successful induction/maintenance of transplantation tolerance, we used MHC class I and II alloreactive TCR-transgenic models to explore the ability of antigen-specific Tregs to control antigen-specific memory T cell responses. Upon coadoptive transfer into RAG-1(-/-) mice, we found that Tregs effectively suppressed the ability of naive T cells to reject skin grafts, but neither antigen-unprimed nor antigen-primed Tregs suppressed rejection by memory T cells. Interestingly, different mechanisms appeared to be active in the ability of Tregs to control naive T cell-mediated graft rejection in the class II versus class I alloreactive models. In the former case, we observed decreased early expansion of effector cells in lymphoid tissue. In contrast, in the class I model, an effect of Tregs on early proliferation and expansion was not observed. However, at a late time point, significant differences in cell numbers were seen, suggesting effects on responding T cell survival. Overall, these data indicate that the relative resistance of both CD4(+) and CD8(+) alloreactive memory T cells to regulation may mediate resistance to tolerance induction seen in hosts with preexisting alloantigen-specific immunity and further indicate the multiplicity of mechanisms by which Tregs may control alloimmune responses in vivo.


Assuntos
Rejeição de Enxerto/imunologia , Memória Imunológica/imunologia , Linfócitos T/imunologia , Animais , Imunidade Inata/imunologia , Subunidade alfa de Receptor de Interleucina-2/imunologia , Camundongos , Modelos Animais , Transplante de Pele/imunologia , Transplante Homólogo/imunologia
11.
Nat Commun ; 11(1): 2198, 2020 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-32366944

RESUMO

The thymus supports multiple αß T cell lineages that are functionally distinct, but mechanisms that control this multifaceted development are poorly understood. Here we examine medullary thymic epithelial cell (mTEC) heterogeneity and its influence on CD1d-restricted iNKT cells. We find three distinct mTEClow subsets distinguished by surface, intracellular and secreted molecules, and identify LTßR as a cell-autonomous controller of their development. Importantly, this mTEC heterogeneity enables the thymus to differentially control iNKT sublineages possessing distinct effector properties. mTEC expression of LTßR is essential for the development thymic tuft cells which regulate NKT2 via IL-25, while LTßR controls CD104+CCL21+ mTEClow that are capable of IL-15-transpresentation for regulating NKT1 and NKT17. Finally, mTECs regulate both iNKT-mediated activation of thymic dendritic cells, and iNKT availability in extrathymic sites. In conclusion, mTEC specialization controls intrathymic iNKT cell development and function, and determines iNKT pool size in peripheral tissues.


Assuntos
Diferenciação Celular/imunologia , Células Epiteliais/imunologia , Células T Matadoras Naturais/imunologia , Timócitos/imunologia , Timo/imunologia , Animais , Antígenos CD1d/genética , Antígenos CD1d/imunologia , Antígenos CD1d/metabolismo , Diferenciação Celular/genética , Linhagem da Célula/genética , Linhagem da Célula/imunologia , Proliferação de Células/genética , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Regulação da Expressão Gênica/imunologia , Ativação Linfocitária/imunologia , Receptor beta de Linfotoxina/genética , Receptor beta de Linfotoxina/imunologia , Receptor beta de Linfotoxina/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células T Matadoras Naturais/citologia , Células T Matadoras Naturais/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Linfócitos T/citologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Timócitos/citologia , Timócitos/metabolismo , Timo/citologia , Timo/metabolismo
12.
Transplantation ; 85(9): 1339-47, 2008 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-18475193

RESUMO

BACKGROUND: The precise role that CD8+ T cells play in the rejection and acceptance of different types of allograft is unclear and has been shown to vary between donor-recipient combinations. METHODS: The response of adoptively transferred CD8+ T cells reactive to the donor alloantigen H2Kb was examined after transplantation of H2Kb liver, kidney, and heart grafts in mice. RESULTS: After transfer of 6 x 10(6) alloreactive CD8+ T cells to T-cell depleted syngeneic mice spontaneous long-term acceptance of liver grafts was observed, whereas kidney and heart grafts were acutely rejected. Within 5 days of liver transplantation, we found that the entire H2Kb-reactive T-cell pool was stimulated to proliferate and differentiate into memory or effector cells that were detectable within lymphoid tissues as well as the liver graft itself. However, despite the generation of effector or memory T cells, liver allografts were accepted, which correlated with the exhaustion or deletion of such cells. In contrast, although activation and proliferation of H2Kb-reactive CD8+ T cells was observed after transplantation of heart or kidney grafts, unactivated, H2Kb-reactive CD8+ T cells were still present in the spleen even long term. Interestingly, differences in the effector function of liver and kidney graft infiltrating donor-reactive CD8+ T cells were not detected after adoptive transfer into immunodeficient mice, despite a reduction in Th1-type cytokines within liver grafts. CONCLUSIONS: The rapid and extensive initial activation and differentiation of donor-reactive CD8+ T cells that occurs after liver transplantation leads to clonal exhaustion or deletion of the alloreactive CD8+ T-cell repertoire resulting in spontaneous tolerance induction.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/imunologia , Transplante de Rim/imunologia , Transplante de Fígado/imunologia , Animais , Linfócitos T CD8-Positivos/citologia , Diferenciação Celular , Transfusão de Linfócitos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Modelos Animais , Transplante Homólogo/imunologia , Transplante Isogênico
13.
Transplantation ; 84(6): 679-81, 2007 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-17893598

RESUMO

Over the past 20 years, natural killer T (NKT) cells have been shown to play an important role in both innate and adaptive immune responses. In this review, the potential role of NKT cells in transplantation will be discussed, particularly their role in rejection and the induction of a state of tolerance.


Assuntos
Rejeição de Enxerto/imunologia , Tolerância Imunológica , Células Matadoras Naturais/imunologia , Transplante de Órgãos , Linfócitos T/imunologia , Humanos
15.
Transplantation ; 82(1): 1-9, 2006 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-16861933

RESUMO

Accumulating evidence suggests that alloreactive memory T cells (Tm) may be generated in transplant recipients that have not previously been exposed to alloantigen through mechanisms such as cross-reactivity and homeostatic proliferation. The presence of Tm correlates with both acute and chronic rejection episodes and, furthermore, may be responsible for the failure to induce tolerance in large animal and clinical settings. A clearer understanding of how Tm function and their requirements to mount an effective response to alloantigen will be key to further attempts to translate tolerance induction protocols from the experimental setting to the clinic.


Assuntos
Rejeição de Enxerto/imunologia , Memória Imunológica , Linfócitos T/imunologia , Tolerância ao Transplante , Animais , Humanos , Transplante Homólogo
16.
J Clin Invest ; 125(12): 4429-46, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26571395

RESUMO

Thrombosis is a common, life-threatening consequence of systemic infection; however, the underlying mechanisms that drive the formation of infection-associated thrombi are poorly understood. Here, using a mouse model of systemic Salmonella Typhimurium infection, we determined that inflammation in tissues triggers thrombosis within vessels via ligation of C-type lectin-like receptor-2 (CLEC-2) on platelets by podoplanin exposed to the vasculature following breaching of the vessel wall. During infection, mice developed thrombi that persisted for weeks within the liver. Bacteria triggered but did not maintain this process, as thrombosis peaked at times when bacteremia was absent and bacteria in tissues were reduced by more than 90% from their peak levels. Thrombus development was triggered by an innate, TLR4-dependent inflammatory cascade that was independent of classical glycoprotein VI-mediated (GPVI-mediated) platelet activation. After infection, IFN-γ release enhanced the number of podoplanin-expressing monocytes and Kupffer cells in the hepatic parenchyma and perivascular sites and absence of TLR4, IFN-γ, or depletion of monocytic-lineage cells or CLEC-2 on platelets markedly inhibited the process. Together, our data indicate that infection-driven thrombosis follows local inflammation and upregulation of podoplanin and platelet activation. The identification of this pathway offers potential therapeutic opportunities to control the devastating consequences of infection-driven thrombosis without increasing the risk of bleeding.


Assuntos
Plaquetas/metabolismo , Lectinas Tipo C/metabolismo , Infecções por Salmonella/metabolismo , Salmonella typhimurium/metabolismo , Trombose/metabolismo , Animais , Plaquetas/patologia , Interferon gama/genética , Interferon gama/metabolismo , Células de Kupffer/metabolismo , Células de Kupffer/patologia , Lectinas Tipo C/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Glicoproteínas da Membrana de Plaquetas/genética , Glicoproteínas da Membrana de Plaquetas/metabolismo , Infecções por Salmonella/complicações , Infecções por Salmonella/genética , Infecções por Salmonella/patologia , Trombose/etiologia , Trombose/genética , Trombose/patologia , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo
17.
Transplantation ; 74(5): 740-3, 2002 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-12352896

RESUMO

BACKGROUND: The effectiveness of anti-CD154 monoclonal antibodies in prolonging the survival of mouse allografts is dependent on the strain combination. In this report, we examined the impact of the donor and the recipient strains on the success of CD40-CD154 blockade. MATERIALS AND METHODS: Cardiac allograft survival was monitored in different donor/recipient strain combinations. Morphometric analyses on the allograft coronary arteries allowed quantification of vessel intimal thickening. RESULTS: Prolonged cardiac allograft survival after the administration of an anti-CD154 monoclonal antibody was found to be dependent on the donor and the recipient strains. The influence of the donor and the recipient strains lay in the ability of CD8 T cells to cause graft rejection despite CD40-CD154 blockade. Elimination of CD8 T cells before transplantation resulted in similar graft prolongation irrespective of the genotype of the donor or the recipient strain. CONCLUSION: These data show that both donor and recipient strains contribute to CD40-CD154-independent CD8 T-cell-mediated rejection.


Assuntos
Antígenos CD40/imunologia , Ligante de CD40/imunologia , Sobrevivência de Enxerto/fisiologia , Transplante de Coração/imunologia , Animais , Transplante de Coração/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Endogâmicos , Especificidade da Espécie , Transplante Homólogo/fisiologia
18.
Transplantation ; 95(4): 527-35, 2013 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-23129000

RESUMO

T cells must be activated before they can elicit damage to allografts, through interaction of their T cell receptor (TCR) with peptide-MHC complex and through accessory molecules. Signaling through accessory molecules or costimulatory molecules is a critical way for the immune system to fine tune T cell activation. An emerging therapeutic strategy is to target selective molecules involved in the process of T cell activation using biologic agents, which do not impact TCR signaling, thus only manipulating the T cells, which recognize alloantigen. Costimulatory receptors and their ligands are attractive targets for this strategy and could be used both to prevent acute graft rejection as well as for maintenance immunosuppression. Therapeutic agents targeting costimulatory molecules, notably belatacept, have made the progression from the bench, through nonhuman primate studies and into the clinic. This overview describes some of the most common costimulatory molecules, their role in T cell activation, and the development of reagents, which target these pathways and their efficacy in transplantation.


Assuntos
Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/efeitos dos fármacos , Imunossupressores/uso terapêutico , Ativação Linfocitária/efeitos dos fármacos , Transplante de Órgãos/efeitos adversos , Linfócitos T/efeitos dos fármacos , Tolerância ao Transplante/efeitos dos fármacos , Animais , Receptores Coestimuladores e Inibidores de Linfócitos T/antagonistas & inibidores , Receptores Coestimuladores e Inibidores de Linfócitos T/metabolismo , Desenho de Fármacos , Rejeição de Enxerto/imunologia , Humanos , Ligantes , Transdução de Sinais/efeitos dos fármacos , Linfócitos T/imunologia , Resultado do Tratamento
19.
Transplantation ; 91(9): 939-45, 2011 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-21378605

RESUMO

T helper (Th) type 17 cells are a recently described CD4 T-cell subset that may contribute to allograft rejection and act as a barrier to the induction of transplant tolerance. This review examines the involvement of Th17 cells in transplant rejection, how immunosuppressive medication may affect their induction and maintenance and the potential plasticity of developing Th17 cells. It also addresses the complex interplay between the Th17 and regulatory T-cell developmental pathways and the susceptibility of Th17 cells to regulation. Despite accumulating evidence, the precise impact of Th17 cells on transplant rejection and the induction of tolerance require further clarification.


Assuntos
Rejeição de Enxerto/etiologia , Rejeição de Enxerto/imunologia , Células Th17/imunologia , Tolerância ao Transplante/imunologia , Animais , Doenças Autoimunes/etiologia , Doenças Autoimunes/imunologia , Resistência a Medicamentos/imunologia , Humanos , Imunossupressores/farmacologia , Camundongos , Modelos Imunológicos , Transdução de Sinais/imunologia , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Células Th17/efeitos dos fármacos , Transplante Homólogo
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