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1.
Nature ; 619(7969): 348-356, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-37344597

RESUMEN

The role of B cells in anti-tumour immunity is still debated and, accordingly, immunotherapies have focused on targeting T and natural killer cells to inhibit tumour growth1,2. Here, using high-throughput flow cytometry as well as bulk and single-cell RNA-sequencing and B-cell-receptor-sequencing analysis of B cells temporally during B16F10 melanoma growth, we identified a subset of B cells that expands specifically in the draining lymph node over time in tumour-bearing mice. The expanding B cell subset expresses the cell surface molecule T cell immunoglobulin and mucin domain 1 (TIM-1, encoded by Havcr1) and a unique transcriptional signature, including multiple co-inhibitory molecules such as PD-1, TIM-3, TIGIT and LAG-3. Although conditional deletion of these co-inhibitory molecules on B cells had little or no effect on tumour burden, selective deletion of Havcr1 in B cells both substantially inhibited tumour growth and enhanced effector T cell responses. Loss of TIM-1 enhanced the type 1 interferon response in B cells, which augmented B cell activation and increased antigen presentation and co-stimulation, resulting in increased expansion of tumour-specific effector T cells. Our results demonstrate that manipulation of TIM-1-expressing B cells enables engagement of the second arm of adaptive immunity to promote anti-tumour immunity and inhibit tumour growth.


Asunto(s)
Linfocitos B , Melanoma , Animales , Ratones , Linfocitos B/citología , Linfocitos B/inmunología , Linfocitos B/metabolismo , Activación de Linfocitos , Melanoma/inmunología , Melanoma/patología , Melanoma/prevención & control , Linfocitos T/citología , Linfocitos T/inmunología , Citometría de Flujo , Melanoma Experimental/inmunología , Melanoma Experimental/patología , Ganglios Linfáticos/citología , Ganglios Linfáticos/inmunología , Presentación de Antígeno , Receptores de Antígenos de Linfocitos B/genética , Análisis de Expresión Génica de una Sola Célula , Carga Tumoral , Interferón Tipo I
2.
Immunol Rev ; 299(1): 31-44, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33484008

RESUMEN

Regulatory B cells (Bregs) ameliorate autoimmune disease and prevent allograft rejection. Conversely, they hinder effective clearance of pathogens and malignancies. Breg activity is mainly attributed to IL-10 expression, but also utilizes additional regulatory mechanisms such as TGF-ß, FasL, IL-35, and TIGIT. Although Bregs are present in various subsets defined by phenotypic markers (including canonical B cell subsets), our understanding of Bregs has been limited by the lack of a broadly inclusive and specific phenotypic or transcriptional marker. TIM-1, a broad marker for Bregs first identified in transplant models, plays a major role in Breg maintenance and induction. Here, we expand on the role of TIM-1+  Bregs in immune tolerance and propose TIM-1 as a unifying marker for Bregs that utilize various inhibitory mechanisms in addition to IL-10. Further, this review provides an in-depth assessment of our understanding of Bregs in transplantation as elucidated in murine models and clinical studies. These studies highlight the major contribution of Bregs in preventing allograft rejection, and their ability to serve as highly predictive biomarkers for clinical transplant outcomes.


Asunto(s)
Enfermedades Autoinmunes , Linfocitos B Reguladores , Animales , Tolerancia Inmunológica , Ratones , Transducción de Señal , Tolerancia al Trasplante
3.
Kidney Int ; 103(4): 749-761, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36436679

RESUMEN

Borderline rejection (BL) in renal transplantation is associated with decreased allograft survival, yet many patients with BL maintain stable graft function. Identifying patients with early BL at risk for shortened allograft survival would allow for timely targeted therapeutic intervention aimed at improving outcomes. 851/1187 patients transplanted between 2013-18 underwent early biopsy (0-4 mos). 217/851 (25%) had BL and were compared to 387/851 without significant inflammation (NI). Serial surveillance and for-cause biopsies and seven-year follow-up were used to evaluate histological and clinical progression. To identify high-risk patients, we examined clinical/histological parameters using regression and non-linear dimensionality reduction (tSNE) and a biomarker based on peripheral blood transitional-1 B cell (T1B) IL-10/TNFα ratio. Compared to NI, early BL was associated with increased progression to late acute rejection (AR; 5-12 mos), premature interstitial fibrosis and tubular atrophy (IFTA) and decreased seven-year graft survival. However, decreased graft survival was limited to BL patients who progressed to late AR or IFTA, and was not influenced by treatment. Although tSNE clustered patients into groups based on clinical factors, the ability of these factors to risk stratify BL patients was modest. In contrast, a low T1B IL-10/TNFα ratio at 3 months identified BL patients at high risk for progression to AR (ROC AUC 0.87) and poor 7-yr graft survival (52% vs. 92%, p=0.003), while BL patients with a high ratio had similar graft survival to patients with NI (91%, p=NS). Thus, progressive early allograft inflammation manifested as BL that progresses to late AR in the first post-transplant year represents a high-risk clinical state for poor allograft outcomes. Such high-risk status can be predicted by the T1B IL-10/TNFα ratio before irreversible scarring sets in, thus allowing timely risk stratification.


Asunto(s)
Enfermedades Renales , Trasplante de Riñón , Humanos , Trasplante de Riñón/efectos adversos , Factor de Necrosis Tumoral alfa , Interleucina-10 , Citocinas , Células Precursoras de Linfocitos B/patología , Fibrosis , Rechazo de Injerto/diagnóstico , Rechazo de Injerto/prevención & control , Rechazo de Injerto/etiología , Enfermedades Renales/patología , Inflamación/patología , Supervivencia de Injerto , Biopsia
4.
Curr Opin Organ Transplant ; 27(5): 385-391, 2022 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-35950881

RESUMEN

PURPOSE OF THE REVIEW: Regulatory B cells (Bregs) play a prominent role in various disease settings. While progress has been hindered by the lack of a specific Breg marker, new findings highlight their role modulating the alloimmune response and promoting allograft survival. RECENT FINDINGS: Herein, we focus on the recent advances in Breg biology and their role in transplantation. We review studies showing that T-cell immunoglobulin and mucin domain 1 (TIM-1) is an inclusive and functional Breg marker in mice that may have human relevance. We highlight the utility of the B cell interleukin-10/tumor necrosis factor-alpha (IL-10/TNFα) ratio in identifying underlying immunological reactivity and predicting clinical outcomes in kidney transplantation. This may identify patients requiring more immunosuppression and provide insight into potential therapeutic approaches that can modulate the Breg: B effector cell (Beff) balance. SUMMARY: Emerging data support Bregs as potent modulators of immune responses in humans. Their ability to promote allograft survival must await development of approaches to expand Bregs in vitro/in vivo . The low IL-10/TNFα ratio reflecting decreased Breg/Beff balance, predicts acute rejection (AR) and poorer outcomes in renal transplantation. It remains to be determined whether this paradigm can be extended to other allografts and whether therapy aiming to correct the relative deficiency of Bregs will improve outcomes.


Asunto(s)
Linfocitos B Reguladores , Trasplante de Riñón , Animales , Biomarcadores , Humanos , Interleucina-10 , Trasplante de Riñón/efectos adversos , Ratones , Células Precursoras de Linfocitos B , Factor de Necrosis Tumoral alfa
5.
Am J Transplant ; 20(1): 52-63, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31355483

RESUMEN

IL-10+ regulatory B cells (Bregs) inhibit immune responses in various settings. While Bregs appear to inhibit inflammatory cytokine expression by CD4+ T cells and innate immune cells, their reported impact on CD8+ T cells is contradictory. Moreover, it remains unclear which effects of Bregs are direct versus indirect. Finally, the subanatomical localization of Breg suppressive function and the nature of their intercellular interactions remain unknown. Using novel tamoxifen-inducible B cell-specific IL-10 knockout mice, we found that Bregs inhibit CD8+ T cell proliferation and inhibit inflammatory cytokine expression by both CD4+ and CD8+ T cells. Sort-purified Bregs from IL-10-reporter mice were adoptively transferred into wild-type hosts and examined by live-cell imaging. Bregs localized to the T:B border, specifically entered the T cell zone, and made more frequent and longer contacts with both CD4+ and CD8+ T cells than did non-Bregs. These Breg:T cell interactions were antigen-specific and reduced subsequent T:DC contacts. Thus, Bregs inhibit T cells through direct cognate interactions that subsequently reduce DC:T cell interactions.


Asunto(s)
Linfocitos B Reguladores/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Comunicación Celular , Células Dendríticas/inmunología , Interleucina-10/fisiología , Linfocitos T Reguladores/inmunología , Animales , Linfocitos B Reguladores/metabolismo , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/metabolismo , Células Dendríticas/metabolismo , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Interleucina-10/metabolismo , Linfocitos T Reguladores/metabolismo
6.
Kidney Int ; 96(1): 202-213, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-31029504

RESUMEN

Post-transplant donor specific antibody (DSA) is associated with poor renal allograft outcomes. However, variable timing of DSA assessment and inclusion of patients who undergo desensitization treatments have hindered our understanding of its consequences and limited its predictive value. Here we prospectively studied non-desensitized patients to determine factors associated with poor four-year outcomes in patients who developed post-transplant DSA. Using serial monitoring, 67 of 294 patients were found to develop DSA by one year. Compared to patients who do not develop DSA, those with DSA exhibit an increased incidence of both clinical and subclinical T-cell-mediated rejection (TCMR). The combination of TCMR plus DSA led to an almost three-fold increase in graft loss compared to either DSA or TCMR alone. Moreover, DSA was associated with higher Banff grade TCMR and chronic changes at one year. Antibody-mediated rejection was uncommon and always associated with TCMR. Amongst factors independently associated with DSA plus TCMR; non-adherence is potentially modifiable. Non-adherence, measured as intra-patient variability of calcineurin trough levels during the first post-transplant year, further risk-stratified patients with DSA plus TCMR such that about 75% of these patients had impending graft loss by four years, whereas adherent patients with DSA plus TCMR had outcomes comparable to other patient groups. Thus, early post-transplant DSA, especially in non-adherent patients, is associated with increased incidence of TCMR and represents a high-risk group of patients who might benefit from targeted therapeutic interventions.


Asunto(s)
Anticuerpos/sangre , Inhibidores de la Calcineurina/uso terapéutico , Rechazo de Injerto/epidemiología , Trasplante de Riñón/efectos adversos , Cumplimiento de la Medicación/estadística & datos numéricos , Linfocitos T/inmunología , Adulto , Anciano , Aloinjertos/inmunología , Aloinjertos/patología , Anticuerpos/inmunología , Biopsia , Femenino , Rechazo de Injerto/sangre , Rechazo de Injerto/inmunología , Rechazo de Injerto/prevención & control , Supervivencia de Injerto/inmunología , Antígenos HLA/inmunología , Humanos , Incidencia , Riñón/inmunología , Riñón/patología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Receptores de Trasplantes/estadística & datos numéricos , Trasplante Homólogo/efectos adversos
7.
Am J Transplant ; 19(8): 2155-2163, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-30803121

RESUMEN

Over the past three decades, improved immunosuppression has significantly reduced T cell-mediated acute rejection rates, but long-term graft survival rates have seen only marginal improvement. The cause of late graft loss has been under intense investigation, and chronic antibody-mediated rejection (AMR) has been identified as one of the leading causes, thus providing a strong rationale for basic science investigation into donor-specific B cells and antibodies in transplantation and ways to mitigate their pathogenicity. In 2018, the American Society of Transplantation launched a community-wide online discussion of Outstanding Questions in Transplantation, and the topic of B cell biology and donor-specific antibody prevention emerged as a major area of interest to the community, leading to a highly engaged dialogue, with comments from basic and translational scientists as well as physicians (http://community.myast.org/communities/community-home/digestviewer). We have summarized this discussion from a bedside to bench perspective and have organized this review into outstanding questions within the paradigm that AMR is a leading cause of graft loss in the clinic, and points of view that challenge aspects of this paradigm. We also highlight opportunities for basic and translational scientists to contribute to the resolution of these questions, mapping important future directions for the transplant research field.


Asunto(s)
Linfocitos B/inmunología , Rechazo de Injerto/etiología , Supervivencia de Injerto/inmunología , Isoanticuerpos/inmunología , Trasplante de Órganos/efectos adversos , Rechazo de Injerto/patología , Humanos
8.
J Immunol ; 199(7): 2585-2595, 2017 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-28848066

RESUMEN

B cells give rise to polarized subsets, including B effector 1 (Be1) cells and regulatory B cells, which can promote or inhibit immune responses through expression of IFN-γ and IL-10, respectively. Such subsets likely explain why B cell depletion can either ameliorate or exacerbate inflammatory diseases; however, these cells remain poorly understood because of the absence of specific markers. Although T cell Ig and mucin domain-containing molecule (TIM)-1 broadly identifies IL-10+ regulatory B cells, no similar markers for Be1 cells have been described. We now show that TIM-4 is expressed by a subset of B cells distinct from those expressing TIM-1. Although TIM-1+ B cells are enriched for IL-10, TIM-4+ B cells are enriched for IFN-γ. TIM-1+ B cells enhanced the growth of B16-F10 melanoma. In contrast, TIM-4+ B cells decreased B16-F10 metastasis and s.c. tumor growth, and this was IFN-γ dependent. TIM-1+ B cells prolonged islet allograft survival in B-deficient mice, whereas TIM-4+ B cells accelerated rejection in an IFN-γ-dependent manner. Moreover, TIM-4+ B cells promoted proinflammatory Th differentiation in vivo, increasing IFN-γ while decreasing IL-4, IL-10, and Foxp3 expression by CD4+ T cells-effects that are opposite from those of TIM-1+ B cells. Importantly, a monoclonal anti-TIM-4 Ab promoted allograft tolerance, and this was dependent on B cell expression of TIM-4. Anti-TIM-4 downregulated T-bet and IFN-γ expression by TIM-4+ B cells and indirectly increased IL-10 expression by TIM-1+ B cells. Thus, TIM-4+ B cells are enriched for IFN-γ-producing proinflammatory Be1 cells that enhance immune responsiveness and can be specifically targeted with anti-TIM-4.


Asunto(s)
Aloinjertos/inmunología , Subgrupos de Linfocitos B/inmunología , Rechazo de Injerto , Interferón gamma/biosíntesis , Melanoma Experimental/inmunología , Proteínas de la Membrana/inmunología , Tolerancia al Trasplante , Animales , Anticuerpos Monoclonales/administración & dosificación , Diferenciación Celular , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Interleucina-10/genética , Interleucina-10/inmunología , Interleucina-4/inmunología , Activación de Linfocitos , Melanoma Experimental/patología , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Metástasis de la Neoplasia , Células TH1/fisiología
9.
Curr Opin Organ Transplant ; 23(5): 524-532, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-30045092

RESUMEN

PURPOSE OF REVIEW: Regulatory B cells (Bregs) are potent inhibitors of the immune system with the capacity to suppress autoimmune and alloimmune responses. Murine transplant models showing that Bregs can promote allograft tolerance are now supported by clinical data showing that patients who develop operational tolerance have higher frequency of Bregs. Breg function has been widely studied resulting in improved understanding of their biology and effector mechanisms. However, our overall understanding of Bregs remains poor due the lack of specific marker, limited knowledge of how and where they act in vivo, and whether different Breg subpopulations exhibit different functions. RECENT FINDINGS: In this review we detail murine and human phenotypic markers used to identify Bregs, their induction, maintenance, and mechanisms of immune suppression. We highlight recent advances in the field including their use as biomarkers to predict allograft rejection, in-vitro expansion of Bregs, and the effects of commonly used immunosuppressive drugs on their induction and frequency. SUMMARY: Clinical data continue to emerge in support of Bregs playing an important role in preventing transplant rejection. Hence, it is necessary for the transplant field to better comprehend the mechanisms of Breg induction and approaches to preserve or even enhance their activity to improve long-term transplant outcomes.


Asunto(s)
Linfocitos B Reguladores/inmunología , Tolerancia al Trasplante/genética , Trasplante/métodos , Humanos
10.
J Bacteriol ; 199(14)2017 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-28461450

RESUMEN

Mutants of Bacillis subtilis that are temperature sensitive for RNA synthesis during sporulation were isolated after selection with a 32P suicide agent. Whole-genome sequencing revealed that two of the mutants carried an identical lesion in the rsbU gene, which encodes a phosphatase that indirectly activates SigB, the stress-responsive RNA polymerase sigma factor. The mutation appeared to cause RsbU to be hyperactive, because the mutants were more resistant than the parent strain to ethanol stress. In support of this hypothesis, pseudorevertants that regained wild-type levels of sporulation at high temperature had secondary mutations that prevented expression of the mutant rsbU gene. The properties of these RsbU mutants support the idea that activation of SigB diminishes the bacterium's ability to sporulate.IMPORTANCE Most bacterial species encode multiple RNA polymerase promoter recognition subunits (sigma factors). Each sigma factor directs RNA polymerase to different sets of genes; each gene set typically encodes proteins important for responses to specific environmental conditions, such as changes in temperature, salt concentration, and nutrient availability. A selection for mutants of Bacillus subtilis that are temperature sensitive for RNA synthesis during sporulation unexpectedly yielded strains with a point mutation in rsbU, a gene that encodes a protein that normally activates sigma factor B (SigB) under conditions of salt stress. The mutation appears to cause RsbU, and therefore SigB, to be active inappropriately, thereby inhibiting, directly or indirectly, the ability of the cells to transcribe sporulation genes.


Asunto(s)
Bacillus subtilis/metabolismo , Proteínas Bacterianas/metabolismo , Regulación Bacteriana de la Expresión Génica/fisiología , Monoéster Fosfórico Hidrolasas/metabolismo , ARN Bacteriano/biosíntesis , Esporas Bacterianas/fisiología , Bacillus subtilis/genética , Proteínas Bacterianas/genética , Etanol/farmacología , Genoma Bacteriano , Calor , Mutación , Fosfatos/metabolismo , Monoéster Fosfórico Hidrolasas/genética , Radioisótopos de Fósforo , Estrés Fisiológico/efectos de los fármacos , Estrés Fisiológico/efectos de la radiación
11.
Kidney Int ; 91(1): 183-195, 2017 01.
Artículo en Inglés | MEDLINE | ID: mdl-28029430

RESUMEN

Human transitional B cells express relatively high IL-10 and low TNF-α levels, which correlate with B regulatory activity in vitro. Herein, we aim to further define B regulatory phenotype and determine whether B regulatory activity can serve as a prognostic marker for renal allograft dysfunction (graft loss or 2-fold fall in estimated glomerular filtration rate). Transitional B cells can be divided into T1 and T2 subsets based on surface phenotype. T1 cells express a significantly higher ratio of IL-10 to TNF-α than T2 cells or other B subsets. When analyzed in 45 kidney transplant recipients at the time of late for-cause biopsy, the T1/T2 ratio was independently associated with allograft dysfunction over the next 5 years. Next, the T1/T2 ratio was examined in an independent set of 97 clinically stable kidney transplant recipients 2 years after transplant. Again, the T1/T2 ratio was strongly and independently associated with allograft dysfunction over the ensuing 5 years. In these clinically quiescent patients, a low T1/T2 ratio identified a 41-patient subgroup in which 35% developed allograft dysfunction, with 25% losing their allografts. However, none of the 56 patients with a high ratio developed graft dysfunction. In both the initial study and validation groups, the T1/T2 ratio was a much stronger predictor of graft dysfunction than donor-specific antibodies or the estimated glomerular filtration rate. Thus, the T1/T2 ratio, a relative measure of expressing an anti-inflammatory cytokine profile, is a novel prognostic marker that might inform individualized immunosuppression.


Asunto(s)
Subgrupos de Linfocitos B/inmunología , Rechazo de Injerto/inmunología , Fallo Renal Crónico/cirugía , Trasplante de Riñón/efectos adversos , Células Precursoras de Linfocitos B/inmunología , Adulto , Anciano , Aloinjertos/inmunología , Anticuerpos/inmunología , Subgrupos de Linfocitos B/metabolismo , Biomarcadores , Biopsia , Femenino , Tasa de Filtración Glomerular , Rechazo de Injerto/epidemiología , Humanos , Tolerancia Inmunológica , Interleucina-10/metabolismo , Riñón/inmunología , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Células Precursoras de Linfocitos B/metabolismo , Medición de Riesgo/métodos , Trasplante Homólogo/efectos adversos , Factor de Necrosis Tumoral alfa/metabolismo
13.
J Am Soc Nephrol ; 25(7): 1575-85, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24610932

RESUMEN

Human B cells with immunoregulatory properties in vitro (Bregs) have been defined by the expression of IL-10 and are enriched in various B-cell subsets. However, proinflammatory cytokine expression in B-cell subsets is largely unexplored. We examined the cytokine profiles of human PBMCs and found that subsets of CD24(hi)CD38(hi) transitional B cells (TrBs), CD24(hi)CD27(+) memory B cells, and naïve B cells express IL-10 and the proinflammatory cytokine TNF-α simultaneously. TrBs had the highest IL-10/TNF-α ratio and suppressed proinflammatory helper T cell 1 (Th1) cytokine expression by autologous T cells in vitro more potently than memory B cells did, despite similar IL-10 expression. Whereas neutralization of IL-10 significantly inhibited TrB-mediated suppression of autologous Th1 cytokine expression, blocking TNF-α increased the suppressive capacity of both memory and naïve B-cell subsets. Thus, the ratio of IL-10/TNF-α expression, a measure of cytokine polarization, may be a better indicator of regulatory function than IL-10 expression alone. Indeed, compared with TrB cells from patients with stable kidney graft function, TrBs from patients with graft rejection displayed similar IL-10 expression levels but increased TNF-α expression (i.e., reduced IL-10/TNF-α ratio), did not inhibit in vitro expression of Th1 cytokines by T cells, and abnormally suppressed expression of Th2 cytokines. In patients with graft dysfunction, a low IL-10/TNF-α ratio in TrBs associated with poor graft outcomes after 3 years of follow-up. In summary, these results indicate that B cell-mediated immune regulation is best characterized by the cytokine polarization profile, a finding that was confirmed in renal transplant patients.


Asunto(s)
Linfocitos B Reguladores/inmunología , Interleucina-10/inmunología , Neoplasias Renales/inmunología , Factor de Necrosis Tumoral alfa/inmunología , Adulto , Linfocitos B Reguladores/metabolismo , Femenino , Rechazo de Injerto/inmunología , Humanos , Interleucina-10/biosíntesis , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/inmunología , Estudios Retrospectivos , Factor de Necrosis Tumoral alfa/biosíntesis
14.
Curr Opin Organ Transplant ; 20(4): 376-84, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-26126193

RESUMEN

PURPOSE OF REVIEW: CD4Foxp3 regulatory T cells (Tregs) are crucial in controlling immunity and self-tolerance. Consequently, in transplantation, Tregs play a central role in inhibiting acute rejection and promoting allograft tolerance. A more complete understanding of Treg biology may lead to novel therapeutic approaches to enhance Treg numbers and function. RECENT FINDINGS: The maintenance of self-tolerance in nonlymphoid tissues requires the differentiation of Tregs in secondary lymphoid organs from naïve-like central Tregs into effector Tregs. Antigen and environmental cues guide this Treg differentiation, which parallels the types of adaptive immune responses taking place, allowing them to enter and function within specific nonlymphoid tissues. In addition to controlling inflammation, tissue-infiltrating Tregs unexpectedly regulate nonimmune processes, including metabolic homeostasis and tissue repair. Finally, Tregs can be directly and specifically targeted in vivo to augment their numbers or enhance their function in both secondary lymphoid organs and nonlymphoid tissues. SUMMARY: Tregs exhibit a previously unrecognized breadth of function, which includes tissue-specific specialization and the regulation of both immune and nonimmune processes. This is of particular importance in transplantation since allo-reactive memory T cells can act directly within the allograft. Thus, therapeutic approaches may need to promote Treg function in transplanted tissue, as well as in secondary lymphoid organs. Such therapy would not only prevent inflammation and acute rejection, but may also promote nonimmune processes within the allograft such as tissue homeostasis and repair.


Asunto(s)
Linfocitos T Reguladores/inmunología , Animales , Antígenos/inmunología , Diferenciación Celular , Humanos , Tolerancia Inmunológica , Tejido Linfoide/inmunología , Trasplante Homólogo
15.
Curr Opin Organ Transplant ; 20(4): 369-75, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-26107970

RESUMEN

PURPOSE OF REVIEW: B cells are known to play a central role in humoral immunity and to boost cellular immunity, however, in a variety of experimental models, B-cell subsets ameliorate inflammation and autoimmune disease, indicating that they can also play a regulatory role. Here, we highlight the advances in regulatory B-cell (Breg) biology of the past year with an emphasis on findings pertinent to transplantation. Several recent observations highlight the relevance to clinical transplantation. Data from at least three independent groups demonstrated that spontaneously tolerant renal transplant recipients exhibit a peripheral blood B-cell signature although the significance of these data remains unclear. Moreover, new data suggest that regulatory B cells may serve as a biomarker for long-term allograft outcomes. Finally, recent evidence suggesting that plasma cells may be an essential component of Bregs raises new concerns about targeting antibody producing cells. RECENT FINDINGS: We describe new information on Breg mechanisms of action to suppress the alloresponse, signals to expand Bregs in vitro, and more functional evidence of Breg involvement in operationally tolerant kidney patients and in maintaining stable allograft function. SUMMARY: Although lymphocyte depletion remains central to tolerance induction therapy, the sparing or expansion of regulatory B cells may be an additional strategy to preempt graft rejection.


Asunto(s)
Linfocitos B/inmunología , Tolerancia Inmunológica , Animales , Rechazo de Injerto/inmunología , Humanos , Inmunidad Celular/inmunología , Inmunidad Humoral , Trasplante Homólogo
16.
J Immunol ; 188(8): 3804-11, 2012 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-22422880

RESUMEN

The efficacy of allogeneic hematopoietic stem cell transplantation is limited by graft-versus-host disease (GVHD). Host hematopoietic APCs are important initiators of GVHD, making them logical targets for GVHD prevention. Conventional dendritic cells (DCs) are key APCs for T cell responses in other models of T cell immunity, and they are sufficient for GVHD induction. However, we report in this article that in two polyclonal GVHD models in which host hematopoietic APCs are essential, GVHD was not decreased when recipient conventional DCs were inducibly or constitutively deleted. Additional profound depletion of plasmacytoid DCs and B cells, with or without partial depletion of CD11b(+) cells, also did not ameliorate GVHD. These data indicate that, in contrast with pathogen models, there is a surprising redundancy as to which host cells can initiate GVHD. Alternatively, very low numbers of targeted APCs were sufficient. We hypothesize the difference in APC requirements in pathogen and GVHD models relates to the availability of target Ags. In antipathogen responses, specialized APCs are uniquely equipped to acquire and present exogenous Ags, whereas in GVHD, all host cells directly present alloantigens. These studies make it unlikely that reagent-based host APC depletion will prevent GVHD in the clinic.


Asunto(s)
Linfocitos B/inmunología , Linfocitos T CD8-positivos/inmunología , Células Dendríticas/inmunología , Enfermedad Injerto contra Huésped/inmunología , Trasplante de Células Madre Hematopoyéticas , Animales , Linfocitos B/patología , Antígeno CD11b/inmunología , Linfocitos T CD8-positivos/patología , Citocinas/biosíntesis , Citocinas/inmunología , Células Dendríticas/patología , Toxina Diftérica , Femenino , Enfermedad Injerto contra Huésped/patología , Humanos , Isoantígenos/inmunología , Depleción Linfocítica , Masculino , Ratones , Ratones Endogámicos C57BL , Quimera por Radiación , Trasplante Homólogo
17.
J Immunol ; 186(5): 2809-18, 2011 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-21270412

RESUMEN

Rapamycin (Rapa), an immunosuppressive drug that acts through mammalian target of Rapa inhibition, broadly synergizes with tolerogenic agents in animal models of transplantation and autoimmunity. Rapa preferentially inhibits conventional CD4(+) Foxp3(-) T cells (Tconv) and promotes outgrowth of CD4(+)Foxp3(+) regulatory T cells (Treg) during in vitro expansion. Moreover, Rapa is widely perceived as augmenting both expansion and conversion of Treg in vivo. However, most quantitative studies were performed in lymphopenic hosts or in graft-versus-host disease models. We show in this study that in replete wild-type mice, Rapa significantly inhibits both homeostatic and alloantigen-induced proliferation of Treg, and promotes their apoptosis. Together, these lead to significant Treg depletion. Tconv undergo depletion to a similar degree, resulting in no change in the percent of Treg among CD4 cells. Moreover, in this setting, there was no evidence of conversion of Tconv into Treg. However, after withdrawal of Rapa, Treg recover Ag-induced proliferation more quickly than Tconv, leading to recovery to baseline numbers and an increase in the percent of Treg compared with Tconv. These findings suggest that the effects of Rapa on Treg survival, homeostasis, and induction, depend heavily on the cellular milieu and degree of activation. In vivo, the resistance of Treg to mammalian target of Rapa inhibition is relative and results from lymphopenic and graft-versus-host disease models cannot be directly extrapolated to settings more typical of solid organ transplantation or autoimmunity. Moreover, these results have important implications for the timing of Rapa therapy with tolerogenic agents designed to increase the number of Treg in vivo.


Asunto(s)
Proliferación Celular , Homeostasis/inmunología , Isoantígenos/fisiología , Transducción de Señal/inmunología , Linfocitos T Reguladores/inmunología , Serina-Treonina Quinasas TOR/fisiología , Animales , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/inmunología , Técnicas de Sustitución del Gen , Homeostasis/efectos de los fármacos , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/inmunología , Recuento de Linfocitos , Depleción Linfocítica , Tejido Linfoide/citología , Tejido Linfoide/efectos de los fármacos , Tejido Linfoide/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Transducción de Señal/efectos de los fármacos , Sirolimus/administración & dosificación , Trasplante de Piel/inmunología , Trasplante de Piel/patología , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/trasplante
18.
Immunol Rev ; 229(1): 271-93, 2009 May.
Artículo en Inglés | MEDLINE | ID: mdl-19426228

RESUMEN

SUMMARY: T cells are central to graft rejection, and therefore preventing T cells from recognizing and destroying allografts remains an important area of transplant research. However, T cells are also required for transplant tolerance; a subset can enforce a state of tolerance by functioning as regulatory cells. As both rejection and regulation directed against alloantigens require T-cell activation, costimulatory molecules undoubtedly play an important role in regulating both processes and ultimately the fate of the allograft. However, costimulation involves an incredibly complex array of interactions that may act contemporaneously or at different times; these interactions can have additive or opposing effects on T-cell activation or differentiation. While some costimulatory molecules mediate activation of naive T cells or generation of memory T cells, others inhibit T-cell activation and promote anergy or apoptosis. Moreover, a given pathway can have diametrically different effects on T-effector cells and regulatory T cells (Tregs). Such a complexity presents both challenges and opportunities in targeting T-cell costimulatory pathways to promote transplant tolerance. In this review article, we provide a summary of recent advances in our understanding of T-cell costimulatory pathways in regulating different phases of the T-cell response in transplant models. We focus specifically on costimulatory molecules in the immunoglobulin (Ig) superfamily, tumor necrosis factor (TNF)/TNF receptor superfamily, and in the emerging T-cell Ig domain and mucin domain family (TIM), highlighting their unique and redundant roles in regulating the T-effector and Treg responses after transplantation. Finally, we summarize emerging approaches toward inducing tolerance by tipping the balance between cytopathic T-effector cells and protective Tregs by selectively targeting specific T-cell costimulatory pathways that are critically involved.


Asunto(s)
Inmunoglobulina G/inmunología , Proteínas de la Membrana/inmunología , Trasplante de Órganos , Linfocitos T Reguladores/inmunología , Tolerancia al Trasplante , Factores de Necrosis Tumoral/inmunología , Animales , Humanos , Activación de Linfocitos , Transducción de Señal
19.
bioRxiv ; 2023 Sep 23.
Artículo en Inglés | MEDLINE | ID: mdl-37790513

RESUMEN

B cells can express pro-inflammatory cytokines that promote a wide variety of immune responses. Here we show that B cells expressing the phosphatidylserine receptor TIM-4, preferentially express not only IL-17A, but also IL-22, IL-6, and GM-CSF - a collection of cytokines reminiscent of pathogenic Th17 cells. Expression of this proinflammatory module requires B cell expression of IL-23R, RORγt and IL-17. IL-17 expressed by TIM-4+ B cells not only enhances the severity of experimental autoimmune encephalomyelitis (EAE) and promotes allograft rejection, but also acts in an autocrine manner to prevent their conversion into IL-10-expressing B cells with regulatory function. Thus, IL-17 acts as an inflammatory mediator and also enforces the proinflammatory activity of TIM-4+ B cells. TIM-4 serves as a broad marker for effector B cells (Beff) that will allow the study of the signals regulating their differentiation and expression of their effector molecules.

20.
Antimicrob Agents Chemother ; 56(5): 2559-64, 2012 May.
Artículo en Inglés | MEDLINE | ID: mdl-22354310

RESUMEN

TP-434 is a novel, broad-spectrum fluorocycline antibiotic with activity against bacteria expressing major antibiotic resistance mechanisms, including tetracycline-specific efflux and ribosomal protection. The mechanism of action of TP-434 was assessed using both cell-based and in vitro assays. In Escherichia coli cells expressing recombinant tetracycline resistance genes, the MIC of TP-434 (0.063 µg/ml) was unaffected by tet(M), tet(K), and tet(B) and increased to 0.25 and 4 µg/ml in the presence of tet(A) and tet(X), respectively. Tetracycline, in contrast, was significantly less potent (MIC ≥ 128 µg/ml) against E. coli cells when any of these resistance mechanisms were present. TP-434 showed potent inhibition in E. coli in vitro transcription/translation (50% inhibitory concentration [IC(50)] = 0.29 ± 0.09 µg/ml) and [(3)H]tetracycline ribosome-binding competition (IC(50) = 0.22 ± 0.07 µM) assays. The antibacterial potencies of TP-434 and all other tetracycline class antibiotics tested were reduced by 4- to 16-fold, compared to that of the wild-type control strain, against Propionibacterium acnes strains carrying a 16S rRNA mutation, G1058C, a modification that changes the conformation of the primary binding site of tetracycline in the ribosome. Taken together, the findings support the idea that TP-434, like other tetracyclines, binds the ribosome and inhibits protein synthesis and that this activity is largely unaffected by the common tetracycline resistance mechanisms.


Asunto(s)
Antibacterianos/farmacología , Escherichia coli/genética , Tetraciclina/farmacología , Tetraciclinas/farmacología , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Unión Competitiva , Escherichia coli/efectos de los fármacos , Escherichia coli/metabolismo , Expresión Génica , Pruebas de Sensibilidad Microbiana , Mutación , Propionibacterium acnes/efectos de los fármacos , Propionibacterium acnes/genética , Propionibacterium acnes/metabolismo , Biosíntesis de Proteínas/efectos de los fármacos , ARN Ribosómico 16S/genética , Ribosomas/genética , Ribosomas/metabolismo , Resistencia a la Tetraciclina/genética , Transformación Bacteriana
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