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1.
Am J Transplant ; 24(8): 1369-1381, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38552961

RESUMEN

Recently published studies in both murine models and a meta-analysis of non-human primate renal transplant studies showed that anti-CD154 reagents conferred a significant survival advantage over CD40 blockers in both animal models and across multiple organs. Here we sought to compare the induction of donor-reactive forkhead box P3+-induced regulatory T cells (Foxp3+ iTreg) in mice treated with anti-CD154 versus anti-CD40 monoclonal antibodies (mAbs). Results indicated that while treatment with anti-CD154 mAb resulted in a significant increase in the frequency of donor-reactive CD4+ Foxp3+ iTreg following transplantation, treatment with anti-CD40 or Cd40 deficiency failed to recapitulate this result. Because we recently identified CD11b as an alternate receptor for CD154 during alloimmunity, we interrogated the role of CD154:CD11b interactions in the generation of Foxp3+ iTreg and found that blockade of CD11b in Cd40-/- recipients resulted in increased donor-reactive Foxp3+ iTreg as compared with CD40 deficiency alone. Mechanistically, CD154:CD11b inhibition decreased interleukin (IL)-1ß from CD11b+ and CD11c+ dendritic cells, and blockade of IL-1ß synergized with CD40 deficiency to promote Foxp3+ iTreg induction and prolong allograft survival. Taken together, these data provide a mechanistic basis for the observed inferiority of anti-CD40 blockers as compared with anti-CD154 mAb and illuminate an IL-1ß-dependent mechanism by which CD154:CD11b interactions prevent the generation of donor-reactive Foxp3+ iTreg during transplantation.


Asunto(s)
Antígenos CD40 , Ligando de CD40 , Factores de Transcripción Forkhead , Ratones Endogámicos C57BL , Linfocitos T Reguladores , Donantes de Tejidos , Linfocitos T Reguladores/inmunología , Animales , Ratones , Factores de Transcripción Forkhead/metabolismo , Antígenos CD40/inmunología , Antígenos CD40/antagonistas & inhibidores , Ligando de CD40/antagonistas & inhibidores , Ligando de CD40/inmunología , Ratones Noqueados , Anticuerpos Monoclonales , Rechazo de Injerto/inmunología , Rechazo de Injerto/prevención & control , Ratones Endogámicos BALB C , Supervivencia de Injerto/inmunología , Supervivencia de Injerto/efectos de los fármacos , Trasplante de Riñón
2.
Immunol Rev ; 258(1): 102-16, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24517428

RESUMEN

Organ transplantation results in the activation of both innate and adaptive immune responses to the foreign antigens. While these responses can be limited with the use of systemic immunosuppressants, the induction of regulatory cell populations may be a novel strategy for the maintenance of specific immunological unresponsiveness that can reduce the severity of the detrimental side effects of current therapies. Our group has extensively researched different regulatory T-cell induction protocols for use as cellular therapy in transplantation. In this review, we address the cellular and molecular mechanisms behind regulatory T-cell suppression and their stability following induction protocols. We further discuss the use of different hematopoietically derived regulatory cell populations, including regulatory B cells, regulatory macrophages, tolerogenic dendritic cells, and myeloid-derived suppressor cells, for the induction of transplantation tolerance in light of new clinical trials developing therapies with some of these populations.


Asunto(s)
Rechazo de Injerto/prevención & control , Trasplante de Células Madre Hematopoyéticas , Trasplante de Órganos , Linfocitos T Reguladores/inmunología , Tolerancia al Trasplante , Traslado Adoptivo , Animales , Rechazo de Injerto/inmunología , Supervivencia de Injerto , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Inmunosupresores/uso terapéutico , Ratones , Trasplante de Órganos/efectos adversos , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/trasplante , Tolerancia al Trasplante/efectos de los fármacos , Resultado del Tratamiento
3.
J Immunol ; 191(4): 1957-64, 2013 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-23858029

RESUMEN

Current models of CD4(+) T cell help suggest a major role for CD154 binding to CD40 expressed on dendritic cells, with a lesser role for direct T:T interactions via CD40 expressed on CD8(+) T cells. However, the contribution of CD8(+) T cell-derived CD40 signals during the donor-reactive T cell response to a transplant has never been studied. In this study, we examined the graft-rejection kinetics and CD4(+) and CD8(+) donor-reactive T cell responses under conditions in which CD40 was genetically ablated only on APC, as well as under conditions in which CD40 was genetically ablated only on donor-reactive CD8(+) T cells. Our results revealed a significant role for CD8(+) T cell-expressed CD40 in the augmentation of donor-reactive CD8(+) T cell responses following transplantation and showed that CD40 expressed on CD8(+) T cells must be inhibited to allow conversion of CD4(+) T cells into induced regulatory T cells. Thus, this study identifies a major role for CD8(+) T cell-derived CD40 signals as a critical switch factor that both promotes optimal differentiation of cytokine-producing CD8(+) effector T cell responses and inhibits the differentiation of Ag-specific Foxp3(+) induced regulatory T cells in vivo.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Antígenos CD40/inmunología , Linfocitos T CD8-positivos/inmunología , Subgrupos de Linfocitos T/inmunología , Linfocitos T Reguladores/inmunología , Tolerancia al Trasplante/inmunología , Traslado Adoptivo , Aloinjertos , Animales , Presentación de Antígeno , Antígenos CD40/antagonistas & inhibidores , Antígenos CD40/deficiencia , Ligando de CD40/antagonistas & inhibidores , Ligando de CD40/inmunología , Células Dendríticas/inmunología , Epítopos de Linfocito T/inmunología , Factores de Transcripción Forkhead/análisis , Listeria monocytogenes/genética , Listeria monocytogenes/inmunología , Listeriosis/inmunología , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ovalbúmina/genética , Ovalbúmina/inmunología , Proteínas Recombinantes/genética , Proteínas Recombinantes/inmunología , Trasplante de Piel
4.
J Immunol ; 189(9): 4387-95, 2012 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-23002440

RESUMEN

Blockade of the CD40/CD154 pathway remains one of the most effective means of promoting graft survival following transplantation. However, the effects of CD40/CD154 antagonism on dendritic cell (DC) phenotype and functionality following transplantation remain incompletely understood. To dissect the effects of CD154/CD40 blockade on DC activation in vivo, we generated hematopoietic chimeras in mice that expressed a surrogate minor Ag (OVA). Adoptive transfer of OVA-specific CD4(+) and CD8(+) T cells led to chimerism rejection, which was inhibited by treatment with CD154 blockade. Surprisingly, CD154 antagonism did not alter the expression of MHC and costimulatory molecules on CD11c(+) DCs compared with untreated controls. However, DCs isolated from anti-CD154-treated animals exhibited a significant reduction in inflammatory cytokine secretion. Combined blockade of inflammatory cytokines IL-6 and IL-12p40 attenuated the expansion of Ag-specific CD4(+) and CD8(+) T cells and transiently inhibited the rejection of OVA-expressing cells. These results suggest that a major effect of CD154 antagonism in vivo is an impairment in the provision of signal three during donor-reactive T cell programming, as opposed to an impact on the provision of signal two. We conclude that therapies designed to target inflammatory cytokines during donor-reactive T cell activation may be beneficial in attenuating these responses and prolonging graft survival.


Asunto(s)
Antígenos CD40/antagonistas & inhibidores , Ligando de CD40/antagonistas & inhibidores , Citocinas/antagonistas & inhibidores , Células Dendríticas/inmunología , Mediadores de Inflamación/antagonistas & inhibidores , Animales , Antígenos CD40/fisiología , Ligando de CD40/fisiología , Pollos , Citocinas/metabolismo , Células Dendríticas/metabolismo , Células Dendríticas/patología , Epítopos de Linfocito T/metabolismo , Mediadores de Inflamación/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Quimera por Radiación , Transducción de Señal/inmunología
5.
Proc Natl Acad Sci U S A ; 108(51): 20701-6, 2011 Dec 20.
Artículo en Inglés | MEDLINE | ID: mdl-22143783

RESUMEN

Blockade of the CD40/CD154 pathway potently attenuates T-cell responses in models of autoimmunity, inflammation, and transplantation. Indeed, CD40 pathway blockade remains one of the most powerful methods of prolonging graft survival in models of transplantation. But despite this effectiveness, the cellular and molecular mechanisms underlying the protective effects of CD40 pathway blockade are incompletely understood. Furthermore, the relative contributions of deletion, anergy, and regulation have not been measured in a model in which donor-reactive CD4(+) and CD8(+) T-cell responses can be assessed simultaneously. To investigate the impact of CD40/CD154 pathway blockade on graft-specific T-cell responses, a transgenic mouse model was used in which recipients containing ovalbumin-specific CD4(+) and CD8(+) TCR transgenic T cells were grafted with skin expressing ovalbumin in the presence or absence of anti-CD154 and donor-specific transfusion. The results indicated that CD154 blockade altered the kinetics of donor-reactive CD8(+) T-cell expansion, delaying differentiation into IFN-γ(+) TNF(+) multifunctional cytokine producers. The eventual differentiation of cytokine-producing effectors in tolerant animals coincided with the emergence of an antigen-specific CD4(+) CD25(hi) Foxp3(+) T-cell population, which did not arise from endogenous natural T(reg) but rather were peripherally generated from naïve Foxp3(-) precursors.


Asunto(s)
Antígenos CD40/biosíntesis , Ligando de CD40/biosíntesis , Factores de Transcripción Forkhead/biosíntesis , Linfocitos T Reguladores/citología , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Citocinas/metabolismo , Supervivencia de Injerto/inmunología , Tolerancia Inmunológica/inmunología , Subunidad alfa del Receptor de Interleucina-2/biosíntesis , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Trasplante de Piel , Linfocitos T Reguladores/inmunología
6.
J Immunol ; 185(4): 2004-8, 2010 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-20631309

RESUMEN

Recent evidence demonstrating that exposure to rapamycin during viral infection increased the quantity and quality of Ag-specific T cells poses an intriguing paradox, because rapamycin is used in transplantation to dampen, rather than enhance, donor-reactive T cell responses. In this report, we compared the effects of rapamycin on the Ag-specific T cell response to a bacterial infection versus a transplant. Using a transgenic system in which the Ag and the responding T cell population were identical in both cases, we observed that treatment with rapamycin augmented the Ag-specific T cell response to a pathogen, whereas it failed to do so when the Ag was presented in the context of a transplant. These results suggest that the environment in which an Ag is presented alters the influence of rapamycin on Ag-specific T cell expansion and highlights a fundamental difference between Ag presented by an infectious agent as compared with an allograft.


Asunto(s)
Linfocitos T CD8-positivos/efectos de los fármacos , Listeria monocytogenes/inmunología , Listeriosis/inmunología , Sirolimus/farmacología , Linfocitos T/inmunología , Traslado Adoptivo , Animales , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Femenino , Citometría de Flujo , Inmunosupresores/farmacología , Interferón gamma/inmunología , Interferón gamma/metabolismo , Selectina L/inmunología , Selectina L/metabolismo , Listeriosis/microbiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Trasplante de Piel/inmunología , Bazo/efectos de los fármacos , Bazo/inmunología , Bazo/metabolismo , Linfocitos T/citología , Linfocitos T/trasplante
7.
Cell Rep ; 39(7): 110819, 2022 05 17.
Artículo en Inglés | MEDLINE | ID: mdl-35584681

RESUMEN

T cell pathology in the skin leads to monocyte influx, but we have little understanding of the fate of recruited cells within the diseased niche, or the long-term impact on cutaneous immune homeostasis. By combining a murine model of acute graft-versus-host disease (aGVHD) with analysis of patient samples, we demonstrate that pathology initiates dermis-specific macrophage differentiation and show that aGVHD-primed macrophages continue to dominate the dermal compartment at the relative expense of quiescent MHCIIint cells. Exposure of the altered dermal niche to topical haptens after disease resolution results in hyper-activation of regulatory T cells (Treg), but local breakdown in tolerance. Disease-imprinted macrophages express increased IL-1ß and are predicted to elicit altered TNF superfamily interactions with cutaneous Treg, and we demonstrate the direct loss of T cell regulation within the resolved skin. Thus, T cell pathology leaves an immunological scar in the skin marked by failure to re-set immune homeostasis.


Asunto(s)
Enfermedad Injerto contra Huésped , Piel , Animales , Humanos , Tolerancia Inmunológica , Macrófagos/metabolismo , Ratones , Monocitos/metabolismo , Piel/metabolismo , Linfocitos T Reguladores
8.
J Immunol ; 181(8): 5313-22, 2008 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-18832687

RESUMEN

Peripheral mechanisms of self-tolerance often depend on the quiescent state of the immune system. To what degree such mechanisms can be engaged in the enhancement of allograft survival is unclear. To examine the role of the PD-1 pathway in the maintenance of graft survival following blockade of costimulatory pathways, we used a single-Ag mismatch model of graft rejection where we could track the donor-specific cells as they developed endogenously and emerged from the thymus. We found that graft-specific T cells arising under physiologic developmental conditions at low frequency were actively deleted at the time of transplantation under combined CD28/CD40L blockade. However, this deletion was incomplete, and donor-specific cells that failed to undergo deletion up-regulated expression of PD-1. Furthermore, blockade of PD-1 signaling on these cells via in vivo treatment with anti-PD-1 mAb resulted in rapid expansion of donor-specific T cells and graft loss. These results suggest that the PD-1 pathway was engaged in the continued regulation of the low-frequency graft-specific immune response and thus in maintenance of graft survival.


Asunto(s)
Antígenos de Diferenciación/inmunología , Linfocitos T CD8-positivos/inmunología , Supervivencia de Injerto/inmunología , Transducción de Señal/inmunología , Trasplante de Piel/inmunología , Tolerancia al Trasplante , Animales , Antígenos CD28/inmunología , Ligando de CD40/inmunología , Ratones , Ratones Noqueados , Receptor de Muerte Celular Programada 1 , Timo/inmunología , Trasplante Homólogo , Regulación hacia Arriba/inmunología
9.
J Clin Invest ; 130(4): 1896-1911, 2020 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-31917684

RESUMEN

Acute graft-versus-host disease (GVHD) is initially triggered by alloreactive T cells, which damage peripheral tissues and lymphoid organs. Subsequent transition to chronic GVHD involves the emergence of autoimmunity, although the underlying mechanisms driving this process are unclear. Here, we tested the hypothesis that acute GVHD blocks peripheral tolerance of autoreactive T cells by impairing lymph node (LN) display of peripheral tissue-restricted antigens (PTAs). At the initiation of GVHD, LN fibroblastic reticular cells (FRCs) rapidly reduced expression of genes regulated by DEAF1, an autoimmune regulator-like transcription factor required for intranodal expression of PTAs. Subsequently, GVHD led to the selective elimination of the FRC population, and blocked the repair pathways required for its regeneration. We used a transgenic mouse model to show that the loss of presentation of an intestinal PTA by FRCs during GVHD resulted in the activation of autoaggressive T cells and gut injury. Finally, we show that FRCs normally expressed a unique PTA gene signature that was highly enriched for genes expressed in the target organs affected by chronic GVHD. In conclusion, acute GVHD damages and prevents repair of the FRC network, thus disabling an essential platform for purging autoreactive T cells from the repertoire.


Asunto(s)
Autoantígenos/inmunología , Autoinmunidad , Enfermedad Injerto contra Huésped/inmunología , Enfermedades Intestinales/inmunología , Ganglios Linfáticos/inmunología , Linfocitos T/inmunología , Animales , Autoantígenos/genética , Enfermedad Injerto contra Huésped/genética , Enfermedad Injerto contra Huésped/patología , Enfermedades Intestinales/genética , Enfermedades Intestinales/patología , Ganglios Linfáticos/patología , Ratones , Ratones Noqueados , Linfocitos T/patología
10.
Sci Immunol ; 4(38)2019 08 23.
Artículo en Inglés | MEDLINE | ID: mdl-31444235

RESUMEN

A dense population of embryo-derived Langerhans cells (eLCs) is maintained within the sealed epidermis without contribution from circulating cells. When this network is perturbed by transient exposure to ultraviolet light, short-term LCs are temporarily reconstituted from an initial wave of monocytes but thought to be superseded by more permanent repopulation with undefined LC precursors. However, the extent to which this process is relevant to immunopathological processes that damage LC population integrity is not known. Using a model of allogeneic hematopoietic stem cell transplantation, where alloreactive T cells directly target eLCs, we have asked whether and how the original LC network is ultimately restored. We find that donor monocytes, but not dendritic cells, are the precursors of long-term LCs in this context. Destruction of eLCs leads to recruitment of a wave of monocytes that engraft in the epidermis and undergo a sequential pathway of differentiation via transcriptionally distinct EpCAM+ precursors. Monocyte-derived LCs acquire the capacity of self-renewal, and proliferation in the epidermis matched that of steady-state eLCs. However, we identified a bottleneck in the differentiation and survival of epidermal monocytes, which, together with the slow rate of renewal of mature LCs, limits repair of the network. Furthermore, replenishment of the LC network leads to constitutive entry of cells into the epidermal compartment. Thus, immune injury triggers functional adaptation of mechanisms used to maintain tissue-resident macrophages at other sites, but this process is highly inefficient in the skin.


Asunto(s)
Células de Langerhans/inmunología , Monocitos/inmunología , Animales , Células Cultivadas , Humanos , Células de Langerhans/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos
11.
JCI Insight ; 3(5)2018 03 08.
Artículo en Inglés | MEDLINE | ID: mdl-29515032

RESUMEN

Graft-versus-host disease (GVHD) is a life-threatening complication of allogeneic stem cell transplantation induced by the influx of donor-derived effector T cells (TE) into peripheral tissues. Current treatment strategies rely on targeting systemic T cells; however, the precise location and nature of instructions that program TE to become pathogenic and trigger injury are unknown. We therefore used weighted gene coexpression network analysis to construct an unbiased spatial map of TE differentiation during the evolution of GVHD and identified wide variation in effector programs in mice and humans according to location. Idiosyncrasy of effector programming in affected organs did not result from variation in T cell receptor repertoire or the selection of optimally activated TE. Instead, TE were reprogrammed by tissue-autonomous mechanisms in target organs for site-specific proinflammatory functions that were highly divergent from those primed in lymph nodes. In the skin, we combined the correlation-based network with a module-based differential expression analysis and showed that Langerhans cells provided in situ instructions for a Notch-dependent T cell gene cluster critical for triggering local injury. Thus, the principal determinant of TE pathogenicity in GVHD is the final destination, highlighting the need for target organ-specific approaches to block immunopathology while avoiding global immune suppression.


Asunto(s)
Reprogramación Celular/inmunología , Enfermedad Injerto contra Huésped/inmunología , Células de Langerhans/inmunología , Piel/inmunología , Linfocitos T Citotóxicos/inmunología , Animales , Antígenos CD/genética , Antígenos CD/metabolismo , Antígenos de Superficie/genética , Antígenos de Superficie/metabolismo , Trasplante de Médula Ósea/efectos adversos , Células Cultivadas , Reprogramación Celular/genética , Modelos Animales de Enfermedad , Femenino , Regulación de la Expresión Génica/inmunología , Enfermedad Injerto contra Huésped/patología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Células de Langerhans/metabolismo , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Masculino , Lectinas de Unión a Manosa/genética , Lectinas de Unión a Manosa/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Familia de Multigenes/genética , Familia de Multigenes/inmunología , Cultivo Primario de Células , Receptores Notch/metabolismo , Piel/citología , Piel/patología , Linfocitos T Citotóxicos/metabolismo , Quimera por Trasplante , Trasplante Homólogo/efectos adversos
12.
PLoS One ; 7(7): e40559, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22792369

RESUMEN

CD154/CD40 blockade combined with donor specific transfusion remains one of the most effective therapies in prolonging allograft survival. Despite this, the mechanisms by which these pathways synergize to prevent rejection are not completely understood. Utilizing a BALB/c (H2-K(d)) to B6 (H2-K(b)) fully allogeneic skin transplant model system, we performed a detailed longitudinal analysis of the kinetics and magnitude of CD8(+) T cell expansion and differentiation in the presence of CD154/CD40 pathway blockade. Results demonstrated that treatment with anti-CD154 vs. DST had distinct and opposing effects on activated CD44(high) CD62L(low) CD8(+) T cells in skin graft recipients. Specifically, CD154 blockade delayed alloreactive CD8(+) T cell responses, while DST accelerated them. DST inhibited the differentiation of alloreactive CD8(+) T cells into multi-cytokine producing effectors, while CD40/CD154 blockade led to the diminution of the KLRG-1(low) long-lived memory precursor population compared with either untreated or DST treated animals. Moreover, only CD154 blockade effectively inhibited CXCL1 expression and neutrophil recruitment into the graft. When combined, anti-CD154 and DST acted synergistically to profoundly diminish the absolute number of IFN-γ producing alloreactive CD8(+) T cells, and intra-graft expression of inflammatory chemokines. These findings demonstrate that the previously described ability of anti-CD154 and DST to result in alloreactive T cell deletion involves both delayed kinetics of T cell expansion and differentiation and inhibited development of KLRG-1(low) memory precursor cells.


Asunto(s)
Ligando de CD40/inmunología , Linfocitos T CD8-positivos/inmunología , Inmunidad Innata , Receptores Inmunológicos/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Traslado Adoptivo , Animales , Anticuerpos Bloqueadores/inmunología , Anticuerpos Monoclonales/inmunología , Ligando de CD40/antagonistas & inhibidores , Linfocitos T CD8-positivos/metabolismo , Quimiocina CCL3/inmunología , Quimiocina CCL3/metabolismo , Quimiocina CCL5/inmunología , Quimiocina CCL5/metabolismo , Quimiocina CXCL1/inmunología , Quimiocina CXCL1/metabolismo , Citocinas/biosíntesis , Supervivencia de Injerto/inmunología , Lectinas Tipo C , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos BALB C , Trasplante de Piel/inmunología , Trasplante Homólogo
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