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1.
J Transl Med ; 13: 123, 2015 Apr 19.
Artículo en Inglés | MEDLINE | ID: mdl-25925868

RESUMEN

BACKGROUND: Adoptive transfer of minor histocompatibility antigen (MiHA)-specific T cells is a promising therapy for patients with hematological cancers. However, the efficacy of the transferred cells is hampered by the acquisition of terminal effector differentiation and exhaustion features during expansion in vitro thus preventing their function and persistence in vivo. Yet, the factors that induce T-cell differentiation and functional impairment in culture remain poorly defined and are likely to vary depending on the method used for expansion. METHODS: Using the clinically relevant HLA-A0201-restricted MiHA HA-1 as well as reagents and procedures that are readily transferable to a clinical environment, we designed a novel culture protocol and defined how exhaustion features appeared in function of time. The optimal time points for the expansion of "fit" MiHA-specific T cells were delineated using phenotypic and functional assessments including KLRG-1 and PD-1 surface markers as well as Ki67 staining and cytokine secretion assays. RESULTS: Following a priming phase, an enrichment step and a rapid expansion stage, our method generates MiHA-specific T-cell lines. Evidence of phenotypic and functional dysfunction appear in function of culture duration, but display different characteristics following the extension of the priming or rapid expansion phases. While repeated antigen exposure during the priming phase induced the decline of the antigen-specific population and the expression of PD-1 and KLRG-1 on antigen-specific CD8+ T cells, the prolongation of an antigen-free expansion phase induced proliferation arrest and the relative loss of antigen-specific cells without impairing polyfunctional cytokine secretion or inducing PD-1 and KLRG-1 expression. A similar pattern was also observed after stimulating a virus-specific memory repertoire, except for the more rapid acquisition of exhaustion features upon repeated antigen exposure. CONCLUSION: Our results offer novel insights on the impact of culture duration on the acquisition of T-cell exhaustion features. Using a new clinical-compliant protocol, we define critical parameters to monitor in order to optimally differentiate and expand MiHA-specific T cells in culture prior to adoptive transfer.


Asunto(s)
Antígenos Estimulantes de Linfocito Menor/inmunología , Linfocitos T/citología , Reactores Biológicos , Línea Celular , Proliferación Celular , Técnicas de Cocultivo , Ensayo de Inmunoadsorción Enzimática , Humanos , Inmunoterapia Adoptiva , Linfocitos T/inmunología
2.
J Reprod Immunol ; 108: 72-82, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25817463

RESUMEN

Paternal antigen-specific regulatory T (PA-specific Treg) cells play an important role in feto-maternal tolerance. To detect the PA-specific Tregs, female BALB/c mice were mated with male DBA/2 mice. Mls Ia antigen on DBA/2 mice is recognized by the T-cell receptor Vß6; thus, CD4(+)Foxp3(+)Vß6(+) cells are recognized as PA-specific Treg cells. CD4(+)CD25(+)Vß6(+) cells effectively suppressed the allo-reactive proliferation of lymphocytes compared with that of CD4(+)CD25(+)Vß6(-) cells. Vß6(+) PA-specific Treg cells expressed CCR4 and CCR5 on their surface. The frequency of Ki67(+) PA-specific Treg cells among Treg cells was significantly increased in draining lymph nodes on day 3.5 post-coitus (pc; 6.8±1.1%, p<0.05) and day 5.5 pc (7.2±1.1%, p<0.05) in allogeneic pregnant mice compared with that in nonpregnant mice (2.7±0.2%). The frequency of Ki67(+) PA-specific Treg cells in the uterus increased significantly after day 5.5 pc in allogeneic pregnant mice compared with that in nonpregnant mice (8.8±2.8% vs. 1.2±1.3%, p<0.05). However, Ki67(-)PA-specific Tregs did not change during pregnancy. To analyze the role of seminal fluid or sperm in Treg expansion, female BALB/c mice were mated with vasectomized DBA/2 male mice (VAS) or seminal vesicle-excised DBA/2 male mice (SVX). The frequency of Ki67(+) PA-specific Treg cells did not increase in draining lymph nodes or uterus in BALB/c×DBA/2 (SVX) allogeneic mating mice. These findings suggest that the priming by seminal fluid is important for the induction of proliferating PA-specific Tregs in uterine-draining lymph nodes just before implantation and pregnant uterus after implantation, resulting in successful implantation and the maintenance of allogeneic pregnancy.


Asunto(s)
Implantación del Embrión/inmunología , Ganglios Linfáticos/inmunología , Semen/inmunología , Linfocitos T Reguladores/inmunología , Útero/inmunología , Animales , Proliferación Celular , Células Cultivadas , Femenino , Factores de Transcripción Forkhead/metabolismo , Isoantígenos/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos DBA , Antígenos Estimulantes de Linfocito Menor/inmunología , Padres , Embarazo , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Receptores CCR4/metabolismo , Receptores CCR5/metabolismo , Vasectomía
3.
Eur J Immunol ; 40(4): 1011-21, 2010 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-20127675

RESUMEN

Cancer-induced immunotolerance mediated by inducible Treg (iTreg) is a major obstacle to cancer immunotherapy. In a basic study of immunotolerance, injection of an endogenous superantigen, i.e. the minor lymphocyte stimulatory (Mls)-1(a), into specific TCR Vbeta8.1-Tg mice enabled generation of anergic CD25(-) iTreg, the immunosuppressive function of which was maintained by IL-10 production via p38-MAPK activation. Interestingly, although p38-chemical inhibitor (p38-inhibitor) is capable of breaking CD25(-) iTreg-induced immunotolerance, the p38-inhibitor had hardly any immunotolerance breaking effect when CD25(+) Treg were present, suggesting that depletion of CD25(+) Treg is necessary for p38-inhibitor to be effective. Peptide OVA(323-339) iv.-injection into its specific TCR-Tg (OT-II) mice also induced adaptive tolerance by iTreg. Peptide immunotherapy with p38-inhibitor after CD25(+) Treg-depletion was performed in an OVA-expressing lymphoma E.G7-bearing tolerant model established by adoptive transfer of OT-II CD25(-) iTreg, which resulted in suppression of tumor growth. Similarly, the antitumor immunity induced by peptide immunotherapy in colon carcinoma CT26-bearing mice, in which the number of IL-10-secreting iTreg is increased, was augmented by treatment with p38-inhibitor after CD25(+) Treg-depletion and resulted in inhibition of tumor progression. These results suggest that simultaneous inhibition of two distinct Treg-functions may be important to the success of cancer immunotherapy.


Asunto(s)
Imidazoles/uso terapéutico , Inmunoterapia Adoptiva , Inmunoterapia/métodos , Interleucina-10/metabolismo , Depleción Linfocítica/métodos , Linfoma no Hodgkin/terapia , Proteínas de Neoplasias/antagonistas & inhibidores , Piridinas/uso terapéutico , Linfocitos T Reguladores/efectos de los fármacos , Escape del Tumor/efectos de los fármacos , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Adaptadoras Transductoras de Señales/biosíntesis , Proteínas Adaptadoras Transductoras de Señales/genética , Secuencia de Aminoácidos , Animales , Anergia Clonal , Factores de Transcripción Forkhead/biosíntesis , Factores de Transcripción Forkhead/genética , Imidazoles/farmacología , Interleucina-10/biosíntesis , Interleucina-10/genética , Subunidad alfa del Receptor de Interleucina-2/análisis , Linfoma no Hodgkin/inmunología , Ratones , Ratones Endogámicos , Ratones Transgénicos , Antígenos Estimulantes de Linfocito Menor/inmunología , Datos de Secuencia Molecular , Proteínas de Neoplasias/fisiología , Ovalbúmina/inmunología , Fragmentos de Péptidos/inmunología , Piridinas/farmacología , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Superantígenos/inmunología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Receptor Toll-Like 9/biosíntesis , Receptor Toll-Like 9/genética , Escape del Tumor/inmunología , Proteínas Quinasas p38 Activadas por Mitógenos/fisiología
4.
Immunobiology ; 215(1): 70-80, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-19249120

RESUMEN

High Mphi:T cell ratios suppress the immune response to the retroviral superantigen Mls by IFNgamma-triggered production of the arg- and trp-consuming enzymes iNOS and IDO. Attempts to reverse suppression by treatment with pro-inflammatory cytokines revealed that IL-6 improved the T cell response to Mls and the pro-hematopoietic cyokines IL-3 and GM-CSF increased suppression. GM-CSF treatment increased Mphi expression of CD80, a ligand for the immune suppressive B7H1 and CTLA-4 receptors. These results illustrate potential strategies for reversing the suppression of cell-mediated immunity characteristic of the high Mphi:T cell ratios found in many tumors.


Asunto(s)
Citocinas/biosíntesis , Tolerancia Inmunológica/efectos de los fármacos , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Activación de Linfocitos/inmunología , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Neoplasias/inmunología , Óxido Nítrico Sintasa de Tipo II/metabolismo , Linfocitos T/efectos de los fármacos , Animales , Antígenos CD/genética , Antígenos CD/inmunología , Antígenos CD/metabolismo , Antígeno B7-1/genética , Antígeno B7-1/inmunología , Antígeno B7-1/metabolismo , Antígeno CTLA-4 , Comunicación Celular/efectos de los fármacos , Comunicación Celular/inmunología , Células Cultivadas , Citocinas/genética , Citocinas/inmunología , Citocinas/farmacología , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Inmunoterapia , Indolamina-Pirrol 2,3,-Dioxigenasa/genética , Indolamina-Pirrol 2,3,-Dioxigenasa/inmunología , Interferón gamma/biosíntesis , Interferón gamma/genética , Interferón gamma/metabolismo , Activación de Linfocitos/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/patología , Ratones , Ratones Endogámicos BALB C , Ratones SCID , Antígenos Estimulantes de Linfocito Menor/inmunología , Neoplasias/metabolismo , Neoplasias/patología , Neoplasias/terapia , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Linfocitos T/patología , Escape del Tumor
5.
J Immunol ; 183(5): 2946-56, 2009 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-19657087

RESUMEN

Regulatory T cells can be used as tools to suppress pathogenic T cells in autoimmunity, graft-vs-host-disease, and transplantation. But even when high numbers of Ag-specific regulatory T cells are available, it is still possible under certain in vivo and in vitro conditions for effector T cells to escape effective control. Current reports suggest that the degree of suppression is modulated by the inflammatory milieu, which can induce resistance to suppression in effector T cells or subvert the inhibitory function of the regulatory T cells. Cells of the innate immune system integrate early signals of injury and infection and have a major impact on the ensuing inflammation. Hence, the modification of these initial events can be key to allowing suppression to dominate. The approach we took here was to test whether the in vivo preactivation of endogenous regulatory T cells with a superantigen could enhance their suppressive potency. We provide evidence that this not only proved effective in expanding the pool of preactivated regulatory T cells but also in preventing the migration of NK cells and granulocytes upon sensitization with matured dendritic cells. The attenuation of innate immune activation was accompanied by linked suppression of adoptively transferred OVA-specific T cells when APC coexpressing OVA and the superantigen were injected. These data suggest that the preactivation of regulatory T cells is a promising approach to increase their potency.


Asunto(s)
Diferenciación Celular/inmunología , Inhibición de Migración Celular/inmunología , Inmunidad Innata , Activación de Linfocitos/inmunología , Fase de Descanso del Ciclo Celular/inmunología , Superantígenos/fisiología , Subgrupos de Linfocitos T/inmunología , Linfocitos T Reguladores/inmunología , Animales , Femenino , Factores de Transcripción Forkhead/biosíntesis , Depleción Linfocítica , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos DBA , Ratones Transgénicos , Antígenos Estimulantes de Linfocito Menor/inmunología , Bazo/citología , Bazo/inmunología , Bazo/trasplante , Subgrupos de Linfocitos T/citología , Subgrupos de Linfocitos T/metabolismo , Linfocitos T Reguladores/metabolismo , Linfocitos T Reguladores/trasplante
6.
Immunobiology ; 209(3): 255-64, 2004.
Artículo en Inglés | MEDLINE | ID: mdl-15518337

RESUMEN

DBA/2J spleen and peritoneal cells were compared for their ability to present the minor lymphocyte stimulatory superantigen Mls-1a. Although capable of Mls presentation in vivo, peritoneal cells were less effective than spleen cells in vitro. This difference was not due to cell concentration or culture duration. Flow cytometric comparison of spleen and peritoneal B cells revealed no significant differences in cell surface markers needed for cognate interaction with T cells. Resolution of peritoneal B cell subsets by cell sorting revealed that even though B-1 cells were capable of Mls presentation, they were less effective than B-2 cells. Mixing experiments showed that B-1 cells did not inhibit B-2 cell presentation of Mls. In contrast, total peritoneal cells inhibited T cell responses to Mls presented by spleen cells. The peritoneal cavity harbors B cells that can present Mls as well as other cells that can suppress this response.


Asunto(s)
Presentación de Antígeno/inmunología , Linfocitos B/inmunología , Antígenos Estimulantes de Linfocito Menor/inmunología , Cavidad Peritoneal/citología , Animales , Femenino , Masculino , Ratones , Ratones Endogámicos , Antígenos Estimulantes de Linfocito Menor/metabolismo , Bazo/citología , Bazo/inmunología
7.
Mol Cell Biol ; 24(16): 6957-66, 2004 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-15282297

RESUMEN

In anergic T cells, T-cell receptor (TCR)-mediated responses are functionally inactivated by negative regulatory signals whose mechanisms are poorly understood. Here, we show that CD4(+) T cells anergized in vivo by superantigen Mls-1(a) express a scaffolding protein, transforming growth factor beta-activated protein kinase 1-binding protein 1 (TAB1), that negatively regulates TCR signaling through the activation of mitogen-activated protein kinase p38 alpha. TAB1 was not expressed in naive and activated CD4(+) T cells. Inhibition of p38 activity in anergic T cells by a chemical inhibitor resulted in the recovery of interleukin 2 (IL-2) and the inhibition of IL-10 secretion. T-cell hybridoma 2B4 cells transduced with TAB1-containing retrovirus (TAB1-2B4 cells) showed activated p38 alpha, inhibited extracellular signal-regulated kinase (ERK) activity, culminating in reduced IL-2 levels and increased IL-10 production. The use of a p38 inhibitor or cotransfection of a dominant-negative form of p38 in TAB1-2B4 cells resulted in the recovery of ERK activity and IL-2 production. These results imply that TAB1-mediated activation of p38 alpha in anergic T cells regulates the maintenance of T-cell unresponsiveness both by inhibiting IL-2 production and by promoting IL-10 production.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales , Linfocitos T CD4-Positivos/fisiología , Proteínas Portadoras/inmunología , Anergia Clonal , Péptidos y Proteínas de Señalización Intracelular , Proteínas Quinasas Activadas por Mitógenos/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Animales , Linfocitos T CD4-Positivos/citología , Proteínas Portadoras/genética , Células Cultivadas , Activación Enzimática , Inhibidores Enzimáticos/metabolismo , Humanos , Interleucina-10/inmunología , Interleucina-2/inmunología , Activación de Linfocitos , Sistema de Señalización de MAP Quinasas/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Ratones Transgénicos , Antígenos Estimulantes de Linfocito Menor/inmunología , Proteínas Quinasas Activadas por Mitógenos/genética , Ratas , Receptores de Antígenos de Linfocitos T/genética , Transducción Genética , Proteínas Quinasas p38 Activadas por Mitógenos
8.
Cell Immunol ; 228(2): 77-80, 2004 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-15219458

RESUMEN

Mice deficient in G-protein subunit alphai2 develop colitis closely resembling human ulcerative colitis when raised on 129SvEv background. When backcrossing the Galphai2-deficiency into a 129SvJBom genetic background, surprisingly, mice did not develop colitis. In vitro stimulation of splenocytes with formalin-killed Staphylococcus aureus resulted in significantly increased production of interleukin-1beta, tumor necrosis factor, and interleukin-12p40 in Galphai2(-/-) as compared to control mice. The enhanced production of pro-inflammatory cytokines was seen in colitis prone as well as in colitis resistant genetic background. A similar outcome was seen upon stimulation with toxic shock syndrome toxin-1, a T cell superantigen, except that Galphai2(-/-) colitis resistant 129SvJBom splenocytes did not show increased production of IL-12p40 as compared to their controls.


Asunto(s)
Colitis/inmunología , Citocinas/biosíntesis , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/deficiencia , Animales , Toxinas Bacterianas/inmunología , Colitis/genética , Colitis/metabolismo , Citocinas/inmunología , Enterotoxinas/inmunología , Femenino , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/inmunología , Interleucina-1/biosíntesis , Interleucina-1/inmunología , Interleucina-10/biosíntesis , Interleucina-10/inmunología , Interleucina-12/biosíntesis , Interleucina-12/inmunología , Subunidad p40 de la Interleucina-12 , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Antígenos Estimulantes de Linfocito Menor/inmunología , Subunidades de Proteína/biosíntesis , Subunidades de Proteína/inmunología , Staphylococcus aureus/inmunología , Estadísticas no Paramétricas , Superantígenos/inmunología , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/inmunología
9.
Immunobiology ; 209(8): 575-84, 2004.
Artículo en Inglés | MEDLINE | ID: mdl-15638126

RESUMEN

Comparative analyses of the ability of lymphoid tissue to present the minor lymphocyte stimulatory (Mls) superantigen Mls-1a in vitro revealed that all tissues containing mature B cells, except peritoneal cavity (PerC) cells, induced Mls-1a-specific T cell activation. Irradiation and mitomycin C treatment, addition of IL-2 and IL-12, and neutralization of IL-10 and TGF-beta did not restore Mls-1a antigen presentation by PerC cells. Co-culture studies revealed that PerC cells actively suppress the T cell response to Mls-1a. PerC cells from severe-combined immune-defective (SCID) mice also suppressed this response indicating that nonlymphoid cells mediate this effect. These results suggest that in addition to antigen processing and presentation, resident peritoneal cavity cells may temper lymphocyte activation.


Asunto(s)
Células Presentadoras de Antígenos/inmunología , Tolerancia Inmunológica , Activación de Linfocitos/inmunología , Antígenos Estimulantes de Linfocito Menor/inmunología , Cavidad Peritoneal/citología , Linfocitos T/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Células Presentadoras de Antígenos/efectos de los fármacos , Células Presentadoras de Antígenos/efectos de la radiación , Apoptosis , Linfocitos B/inmunología , Comunicación Celular/inmunología , Técnicas de Cocultivo , Citocinas/inmunología , Citocinas/farmacología , Citocinas/fisiología , Femenino , Tejido Linfoide/citología , Tejido Linfoide/inmunología , Masculino , Ratones , Ratones Endogámicos , Ratones Mutantes , Mitomicina/farmacología
10.
Proc Natl Acad Sci U S A ; 97(24): 13257-62, 2000 Nov 21.
Artículo en Inglés | MEDLINE | ID: mdl-11069296

RESUMEN

We have found suppressor T cells that inhibit the proliferative response of naive CD4(+) T cells in T cell receptor (TCR) Vbeta8.1 transgenic mice rendered tolerant in vivo by inoculation of Mls-1(a)-positive cells. This suppression was mediated by CD4(+) T cells but not by CD8(+) T cells or double-negative (DN) cells, and splenic CD4(+) T cells from tolerant mice displayed a greater suppression than lymph node CD4(+) T cells. Cell contact was required for efficient suppression, and known inhibitory cytokines such as IL-4, IL-10, and transforming growth factor beta were not involved. Suppressor T cells inhibited IL-2 production by naive CD4(+) T cells, and the addition of exogenous IL-2 diminished the suppressed activity while having little activity on tolerant T cells. Suppression was abolished by the elimination of CD25(+) T cells in the tolerant CD4(+) T cell subset. CD25(+)CD4(+) T cells suppressed the proliferative response of the residual fraction of the nonanergic population, namely, 6C10(+)CD4(+) T cells still present in the tolerant mice. However, 6C10(-)CD4(+) T cells still had reduced reactivity to Mls-1(a) even after CD25(+)CD4(+) T cells were removed and exogenous IL-2 was added. Suppressor cells appear to affect only residual nonanergic cells in situ, thereby facilitating the maintenance of the unresponsive state in vivo. These data provide a framework for understanding suppressor T cells and explain the difficulties and variables in defining their activity in other systems, because suppressor T cells apparently control only a small population of nonanergic cells in the periphery and may be viewed as a homeostatic mechanism.


Asunto(s)
Genes Codificadores de la Cadena beta de los Receptores de Linfocito T , Antígenos Estimulantes de Linfocito Menor/inmunología , Subgrupos de Linfocitos T/inmunología , Linfocitos T Reguladores/inmunología , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Células Cultivadas , Tolerancia Inmunológica , Ganglios Linfáticos/inmunología , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Ratones Transgénicos , Bazo/inmunología
11.
Biol Blood Marrow Transplant ; 6(5A): 529-36, 2000.
Artículo en Inglés | MEDLINE | ID: mdl-11071258

RESUMEN

Understanding the cellular mechanisms that lead to graft-versus-host disease (GVHD) may lead to alternative approaches in the prevention or therapy of this disease process. In this manuscript, we investigated the mechanisms of action of the immunosuppressive drug rapamycin for the prevention of GVHD. GVHD-free long-term survival was achieved in BALB/c (H2d, Mls-2a, Mls-3a) recipients of B10.D2/nSnJ (H-2d, Mls-2a, Mls-3a) bone marrow and spleen cells after a 30-day course of high-dose rapamycin (5 mg/kg per day). Low responses to recipient and third-party cells in a mixed lymphocyte reaction (MLR) were observed as well as decreased mature T-cell numbers in the spleen. This low response was not due to defective interleukin (IL)-2 production, because exogenous IL-2 did not improve the responses in the MLR. However, GVHD-free long-term survival was associated with a large number of infiltrating mononuclear cells in the target organs of GVHD. This observation suggested the possibility that these cells were responsible for suppressing the immune response. Regulatory cells, which could suppress both antirecipient and third-party responses in vitro, were demonstrated to be present in the spleens of these GVHD-free long-term survivors. These results suggest that in addition to impaired cellular immune function, the presence of non-specific regulatory cells (ie, suppression) may contribute to maintenance of GVHD-free long-term survival induced by short-course rapamycin.


Asunto(s)
Enfermedad Injerto contra Huésped/prevención & control , Inmunosupresores/uso terapéutico , Sirolimus/uso terapéutico , Animales , Trasplante de Médula Ósea/efectos adversos , Trasplante de Células/efectos adversos , Técnicas de Cocultivo , Citometría de Flujo , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/patología , Inmunosupresores/farmacología , Recuento de Linfocitos , Prueba de Cultivo Mixto de Linfocitos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Antígenos Estimulantes de Linfocito Menor/inmunología , Quimera por Radiación , Sirolimus/farmacología , Piel/patología , Organismos Libres de Patógenos Específicos , Bazo/citología , Bazo/inmunología , Bazo/patología , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Citotóxicos/inmunología , Trasplante Homólogo/efectos adversos
12.
Ter Arkh ; 72(11): 62-7, 2000.
Artículo en Ruso | MEDLINE | ID: mdl-11229316

RESUMEN

AIM: To characterize mixed lymphocyte culture (MLC) reaction used for determination of donor-recipient compatibility before bone marrow transplantation to patients with hematological malignancies and to assess the reaction significance. MATERIAL AND METHODS: The analysis was made of compatibility testing in MLC standard reaction performed in 134 patients with hematological malignancies with HLA-A, -B identical donors-sibs and in 5 patients with haploid identical donors. RESULTS: Out of 134 patients, 22(91%) appeared compatible to donor sibs in MLC reaction, 12(9%) patients were incompatible. Mean RR for MLC-compatible couples made up: in RvD direction 77 +/- 0.17%, DvR 2.61 +/- 0.32%. 93% of RR values ranged from +15 to -15%, the rest--from +25% to -25%. Bone marrow transplantation was made in 83 patients. Graft retention was observed in 77(93%) patients. Acute and chronic graft versus host reaction developed in 15 and 17 patients, respectively. CONCLUSION: An optimal protocol is proposed for examination of compatibility donor-recipient in MLC reaction in patients with hematological malignancies. It is intended for allogenic bone marrow transplantation in hematological departments.


Asunto(s)
Trasplante de Médula Ósea , Neoplasias Hematológicas/terapia , Histocompatibilidad/inmunología , Antígenos Estimulantes de Linfocito Menor/inmunología , Adolescente , Adulto , Trasplante de Médula Ósea/inmunología , Niño , Femenino , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/prevención & control , Antígenos HLA-A/inmunología , Antígenos HLA-B/inmunología , Neoplasias Hematológicas/inmunología , Humanos , Prueba de Cultivo Mixto de Linfocitos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Donantes de Tejidos , Trasplante Homólogo
13.
Eur J Immunol ; 29(9): 2826-34, 1999 09.
Artículo en Inglés | MEDLINE | ID: mdl-10508257

RESUMEN

Peptide-pulsed mouse dendritic cells (DC) primed peptide-specific CD8+ cytotoxic T cell responses very effectively if they expressed minor histocompatibility antigens, which could stimulate a CD4+ T helper cell response. These DC could also prime most syngeneic mice, although there was no deliberate immunization for help (the DC were prepared in syngeneic mouse serum, to avoid any response to fetal calf serum antigens). In contrast, DC were unable to prime MHC class II-deficient mice for cytotoxic responses to the classical helper-dependent antigens Qa1a and HY. More strikingly, Balb.B DC failed to prime B6 MHC class II-deficient mice for cytotoxic responses to Balb minor antigens, even though these two strains differ at more than 40 minor histocompatibility loci. When peptide-pulsed DC were prepared without enzymes (used to release DC from lymphoid tissues), they failed to prime the majority of normal syngeneic mice, even though they expressed high levels of B7 and ICAM-1 co-stimulatory molecules, suggesting that help was provided by responses to antigens in the enzyme cocktail. The enzyme treatment itself did not provide signals that could substitute for help, since DC prepared with enzymes could not prime MHC class II-deficient mice. The observation that highly immunogenic minor-incompatible DC failed to prime MHC class II-deficient mice suggests that in the absence of inflammatory signals, even strong antigens cannot stimulate CD8+ T cell responses without help.


Asunto(s)
Antígenos/inmunología , Células Dendríticas/inmunología , Linfocitos T Citotóxicos/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Células Dendríticas/metabolismo , Femenino , Citometría de Flujo , Antígenos H-2/inmunología , Antígenos de Histocompatibilidad Clase II/inmunología , Masculino , Ratones , Ratones Congénicos , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Antígenos Estimulantes de Linfocito Menor/inmunología , Péptidos/metabolismo
15.
Immunology ; 95(1): 18-25, 1998 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-9767452

RESUMEN

A limited T-cell receptor (TCR) Vbeta repertoire employed by autoreactive T cells may be related to the development and course of autoimmune diseases. Vbeta repertoire skewing has been observed not only in man, but also in animal models of several human autoimmune diseases, such as MRL-lpr mice, which spontaneously develop a systemic lupus erythematosus (SLE)-like disease. Murine chronic graft-versus-host disease (GVHD) is an inducible model for SLE, involving direct interaction between donor T cells and recipient B cells. It is not known whether Vbeta-specific T-cell subsets are pathogenically involved in this model. Retroviral superantigens such as Mls-1 are known to have a profound impact on the TCR Vbeta repertoire in mice. Restriction of the peripheral TCR repertoire may result from intrathymic expression of Mls-1, which causes deletion of T cells expressing Vbeta6, -7, -8.1, or -9. Mls-1 incompatibility between donor and recipient can be used to determine the involvement of these TCR Vbeta families in GVHD. In the present study we induced GVHD in several strain combinations to investigate TCR Vbeta gene expression during GVHD, and the effect of Mls-1 incompatibility on the TCR Vbeta repertoire. TCR Vbeta gene expression was determined using an RNase protection assay. Our results indicate that T cells expressing the Vbeta2 or Vbeta16 chain play an important pathogenetic role, while T cells bearing the Vbeta1 or Vbeta6 chain may be related to self-limitation of the lupus-like disease in this model.


Asunto(s)
Genes Codificadores de la Cadena beta de los Receptores de Linfocito T , Nefritis Lúpica/genética , Linfocitos T/metabolismo , Animales , Cruzamiento , Ensayo de Inmunoadsorción Enzimática , Expresión Génica , Enfermedad Injerto contra Huésped/genética , Enfermedad Injerto contra Huésped/inmunología , Inmunohistoquímica , Nefritis Lúpica/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos DBA , Ratones Endogámicos , Antígenos Estimulantes de Linfocito Menor/inmunología , ARN/análisis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
16.
Transpl Immunol ; 5(2): 75-82, 1997 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-9269028

RESUMEN

When lethally irradiated AKR (Mls-1a) mice were reconstituted with bone marrow (BM) cells plus a small number (0.5%) of mature T cells from allogeneic B10.AQR or B10 (Mls-1b) mice and minor GVHR was induced in the recipients, almost complete donor chimerism was accomplished in the early stages after reconstitution. By contrast, in irradiated AKR mice reconstituted with T cell-depleted BM cells alone from B10 or B10.AQR mice, radio-resistant T cells of recipient origin persisted for a relatively long period in peripheral lymphoid tissues. In this paper the influence of residual T cells in the chimeric mice on generation of the T cell repertoire derived from donor BM is discussed. It will be demonstrated that the recipient (AKR) T cells are capable of producing Mls-1a antigens (Ag) after lethal irradiation in vivo. These recipient T cells eventually induce clonal elimination of Mls-1a reactive V beta 6+, V beta 8.1+ and V beta 9+ T cells derived from developing thymocytes of donor BM origin. The Mls-1a reactive T cells are not eliminated in GVHR chimeras in which recipient T cells are absent. However, V beta 5+ T cells reactive to I-E plus Etc-1 Ag are deleted in the chimeras undergoing GVHR. These results indicate that recipient cells which produce tissue-specific antigens (tolerogens) should be taken into consideration when generation of the T cell repertoire of donor origin following allogeneic BM transplantation is investigated.


Asunto(s)
Trasplante de Médula Ósea/inmunología , Reacción Injerto-Huésped/inmunología , Tolerancia Inmunológica , Antígenos Estimulantes de Linfocito Menor/inmunología , Linfocitos T/inmunología , Animales , Antígenos CD4/análisis , Antígenos CD4/inmunología , Antígenos CD8/análisis , Antígenos CD8/inmunología , Quimera/inmunología , Supresión Clonal , Prueba de Cultivo Mixto de Linfocitos , Ratones , Ratones Endogámicos AKR , Ratones Endogámicos , Receptores de Antígenos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/inmunología , Timo/inmunología , Factores de Tiempo
17.
Blood ; 89(1): 49-54, 1997 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-8978276

RESUMEN

Graft failure is a mortal complication in allogeneic bone marrow transplantation (BMT); T cells and natural killer cells are responsible for graft rejection. However, we have recently demonstrated that the recruitment of donor-derived stromal cells prevents graft failure in allogeneic BMT. This finding prompted us to examine whether a major histocompatibility complex (MHC) restriction exists between hematopoietic stem cells (HSCs) and stromal cells. We transplanted bone marrow cells (BMCs) and bones obtained from various mouse strains and analyzed the cells that accumulated in the engrafted bones. Statistically significant cell accumulation was found in the engrafted bone, which had the same H-2 phenotype as that of the BMCs, whereas only few cells were detected in the engrafted bones of the third-party H-2 phenotypes during the 4 to 6 weeks after BMT. Moreover, the BMCs obtained from the MHC-compatible bone showed significant numbers of both colony-forming units in culture (CFU-C) and spleen colony-forming units (CFU-S). These findings strongly suggest that an MHC restriction exists between HSCs and stromal cells.


Asunto(s)
Trasplante de Médula Ósea/inmunología , Médula Ósea/inmunología , Trasplante Óseo/inmunología , Tejido Conectivo/inmunología , Antígenos H-2/inmunología , Células Madre Hematopoyéticas/inmunología , Animales , Células de la Médula Ósea , Movimiento Celular , Ensayo de Unidades Formadoras de Colonias , Femenino , Histocompatibilidad , Inmunofenotipificación , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Antígenos Estimulantes de Linfocito Menor/inmunología , Quimera por Radiación , Trasplante Homólogo/inmunología
18.
Eur J Immunol ; 27(12): 3253-8, 1997 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-9464813

RESUMEN

Previous studies showed that activation of CD4+ T cells with mouse mammary tumor virus-encoded Mls(a) superantigens induces strong proliferative responses and interleukin-2 production but fails to elicit typical early T cell receptor (TCR)-mediated signal transduction events, such as hydrolysis of polyphosphoinositides (PI) or an increase in intracellular calcium. Here we show that the failure of Mls(a) antigen to activate PI hydrolysis applies when resting B cells are used as antigen-presenting cells (APC). By contrast, when Mls(a)-bearing B cells are activated for 24 h by exposure to lipopolysaccharide or, more importantly, to Mls(a)-reactive T cells or anti-CD40 antibodies the cells develop the capacity to elicit easily detectable PI turnover. These studies demonstrate that, for B cells as APC, the initiation of certain TCR-associated signal transduction pathways can depend on activation of the APC. The data suggest that cross talk between T cells and resting B cells can suffice to generate competent B APC and lead to the delayed initiation of signaling pathways important in T cell responses.


Asunto(s)
Presentación de Antígeno , Linfocitos B/inmunología , Cooperación Linfocítica , Antígenos Estimulantes de Linfocito Menor/inmunología , Transducción de Señal/inmunología , Linfocitos T/inmunología , Animales , Fosfatos de Inositol/inmunología , Ratones , Superantígenos/inmunología
19.
Eur J Immunol ; 26(10): 2517-28, 1996 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-8898968

RESUMEN

In the present work, we explored the cytokine-dependent regulation of bone marrow-derived mast cell (BMMC) antigen-presenting cell (APC) function, and co-stimulation requirements, and analyzed the nature of antigens presented to T cells. We observed an up-regulation of the APC function of mast cells induced by granulocyte/macrophage-colony-stimulating factor (GM-CSF) and a complete abrogation by interferon (IFN)-gamma. Expression of co-stimulatory molecules CD80 and CD86 was suggested by the ability of mast cells to activate purified lymph node-derived T cells. Indeed, addition of the fusion protein mCTLA4-Ig strongly inhibited antigen presentation by mast cells to normal T cells and to the T cell hybridoma 3DO-54.8. The regulatory mechanisms of APC function by GM-CSF and IFN-gamma were investigated by measuring CD80 and CD86 transcripts in mast cells. GM-CSF-treated must cells showed a strong increase in the expression of both CD80 and CD86 transcripts, whereas in IFN-gamma-treated mast cells, this expression was completely abrogated. Thus, up- and down-regulation of CD80 and CD86 expression by GM-CSF and IFN-gamma is directly correlated to the APC function. In addition, we analyzed antigen presentation by mast cells of endogenous self-antigens. Mast cells failed to activate anti-I-A or anti-I-E-specific T cell hybridomas and alloreactive T cells in primary mixed lymphocyte reactions (MLR). Furthermore, mast cells did not present the mouse beta 2-microglobulin (m beta 2-m) peptide 25-40, constitutively expressed on B cells. However, mast cells, especially those treated with GM-CSF, activated an anti-m beta 2-m-specific T cell hybridoma in the presence of exogenous peptide. The minor lymphocyte-stimulating antigen-1 Mls-1a is a viral superantigen (vSAG) encoded by the the mouse mammary tumor provirus-7 (MMTV-7). Mast cells, despite a reasonable amount of major histocompatibility complex class II on the cell surface and the presence of MMTV transcripts predicted to encode the vSAG, cannot stimulate in vivo or in vitro V beta 6+ T cells specific for Mls-1a. In contrast, mast cells could present the exogenous bacterial SAG, staphylococcal enterotoxin B (SEB), to specific V beta 8+ T cells. The selective ability of mast cells to present exogenous antigens may have physiological relevance in that mast cells could participate in immune response regulatory mechanisms by discriminating self from nonself.


Asunto(s)
Células Presentadoras de Antígenos/inmunología , Antígenos CD/fisiología , Antígenos/metabolismo , Antígeno B7-1/fisiología , Linfocitos T CD4-Positivos/inmunología , Mastocitos/inmunología , Glicoproteínas de Membrana/fisiología , Animales , Antígeno B7-2 , Células de la Médula Ósea , Expresión Génica , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Antígenos de Histocompatibilidad Clase II/inmunología , Interferón gamma/farmacología , Interleucina-2/biosíntesis , Activación de Linfocitos , Ratones , Ratones Endogámicos , Antígenos Estimulantes de Linfocito Menor/inmunología , ARN Mensajero/genética , Proteínas Recombinantes , Superantígenos/inmunología , Transcripción Genética
20.
Curr Opin Immunol ; 8(4): 498-502, 1996 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-8794013

RESUMEN

Superantigens of mouse mammary tumor virus induce a strong cognate interaction between T cells and B cells. In addition to amplifying the virus-infected B-cell pool, this superantigen-driven interaction leads to the differentiation of virus-specific B cells into plasma cells. Successful interaction between T cells and B cells is required for completion of the viral life cycle.


Asunto(s)
Linfocitos B/inmunología , Cooperación Linfocítica/inmunología , Virus del Tumor Mamario del Ratón/inmunología , Linfocitos T/inmunología , Animales , Ratones , Antígenos Estimulantes de Linfocito Menor/inmunología , Infecciones por Retroviridae/inmunología , Superantígenos/inmunología , Infecciones Tumorales por Virus/inmunología
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