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2.
Eur J Immunol ; 43(9): 2255-8, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-24037677

RESUMEN

Graft-versus-host disease (GVHD) is a major complication associated with allogeneic bone marrow transplantation (BMT). Recent advances in the treatment of lymphoid malignancies with BMT include exploring mechanisms that can inhibit GVHD while maintaining graft-versus-leukemic (GVL) effects. In this issue of the European Journal of Immunology, Yu et al. [Eur. J. Immunol. 2013.43: 2327-2337] demonstrate efficient separation of GVHD and GVL by abrogating c-Rel in T cells. Intrinsic c-Rel deficiency in T cells resulted in complete protection against GVHD in both major and minor histocompatibility mismatched murine models of BMT. Protection against GVHD was associated with a decreased presence of Th1 and Th17 cells with a concomitant increase in Treg-cell numbers. Interestingly, an intrinsic defect of c-Rel also resulted in decreased expression of the Th1-associated chemokine receptor CXCR3. Finally, the absence of c-Rel maintained GVL effects with significant tumor clearance in murine recipients. These data suggest that specific targeting of the T-cell-specific transcription factor c-Rel can inhibit GVHD while maintaining GVL effects.


Asunto(s)
Trasplante de Médula Ósea/inmunología , Enfermedad Injerto contra Huésped/inmunología , Proteínas Proto-Oncogénicas c-rel/metabolismo , Linfocitos T Reguladores/inmunología , Animales
3.
Blood ; 122(14): 2346-57, 2013 Oct 03.
Artículo en Inglés | MEDLINE | ID: mdl-23954891

RESUMEN

Estrogen deficiency expands hemopoietic stem and progenitor cells (HSPCs) and mature blood lineages, but the involved mechanism and the affected HSPC populations are mostly unknown. Here we show that ovariectomy (ovx) expands short-term HSPCs (ST-HSPCs) and improves blood cell engraftment and host survival after bone marrow (BM) transplantation through a dual role of the T-cell costimulatory molecule CD40 ligand (CD40L). This surface receptor is required for ovx to stimulate T-cell production of Wnt10b, a Wnt ligand that activates Wnt signaling in HSPCs and stromal cells (SCs). Moreover, CD40L is required for ovx to increase SC production of the hemopoietic cytokines interleukin (IL)-6, IL-7, and granulocyte macrophage-colony-stimulating factor. Attesting to the relevance of CD40L and Wnt10b, ovx fails to expand ST-HSPCs in CD40L-null mice and in animals lacking global or T-cell expression of Wnt10b. In summary, T cells expressed CD40L, and the resulting increased production of Wnt10b and hemopoietic cytokines by T cells and SCs, respectively, plays a pivotal role in the mechanism by which ovx regulates hemopoiesis. The data suggest that antiestrogens may represent pharmacological targets to improve ST-HSPC function through activation of the microenvironment.


Asunto(s)
Ligando de CD40/biosíntesis , Hematopoyesis/fisiología , Células Madre Hematopoyéticas/metabolismo , Ovariectomía , Linfocitos T/metabolismo , Proteínas Wnt/biosíntesis , Animales , Trasplante de Médula Ósea/inmunología , Femenino , Citometría de Flujo , Células Madre Hematopoyéticas/inmunología , Ratones , Ratones Noqueados , Linfocitos T/inmunología , Proteínas Wnt/inmunología
4.
Curr Opin Organ Transplant ; 18(4): 402-7, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23838644

RESUMEN

PURPOSE OF REVIEW: Although numerous experimental models to induce allograft tolerance have been reported, it has been difficult to translate these basic studies to clinical transplantation. However, successful induction of tolerance in HLA-mismatched kidney transplantation has recently been reported. In this review, recent progress in tolerance induction in preclinical (nonhuman primates) and clinical transplantation is summarized. RECENT FINDINGS: Among many clinical trials to induce renal allograft tolerance, success has so far been achieved only by combining donor bone marrow with organ transplantation. Induction of renal allograft tolerance by transient or durable mixed chimerism has been reported in HLA-matched or mismatched kidney transplant recipients. More recently, renal allograft tolerance by induction of full donor chimerism has also been reported using a more intensified preparative conditioning regimen. SUMMARY: Durable allograft tolerance has been achieved by induction of hematopoietic chimerism in clinical kidney transplantation, with outstanding long-term results in successful cases. However, these approaches have been associated with higher early complications than are seen following transplantation with conventional immunosuppression. Improvements in the consistency and safety of tolerance induction and extension of successful protocols to other organs will be the next steps in bringing tolerance to a wider range of clinical applications.


Asunto(s)
Trasplante de Médula Ósea/inmunología , Quimerismo , Tolerancia Inmunológica/fisiología , Trasplante de Riñón/inmunología , Quimera por Trasplante/inmunología , Tolerancia al Trasplante/inmunología , Antígenos HLA/inmunología , Humanos
6.
J Immunol ; 191(2): 688-98, 2013 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-23752612

RESUMEN

NK subsets have activating and inhibitory receptors that bind MHC-I. Ly49A is a mouse inhibitory receptor that binds with high affinity to H2(d) in both a cis- and trans-manner. Ly49A cis-associations limit trans-interactions with H2(d)-expressing targets as well as mAb binding. We demonstrate that cis-interactions affect mAb effector functions. In vivo administration of anti-Ly49A depleted NK cells in H2(b) but not H2(d) mice. Despite lack of depletion, in vivo treatment with anti-Ly49A reduced NK killing capabilities and inhibited activation, partially due to its agonistic effect. These data explain the previously described in vivo effects on bone marrow allograft rejection observed with anti-Ly49A treatment in H2(d)-haplotype mice. However, prior treatment of mice with poly(I:C) or mouse CMV infection resulted in increased Ly49A expression and Ly49A(+) NK cell depletion in H2(d) mice. These data indicate that, although Ly49 mAbs can exert similar in vivo effects in mice with different MHC haplotypes, these effects are mediated via different mechanisms of action correlating with Ly49A expression levels and can be altered within the same strain contingent on stimuli. This illustrates the marked diversity of mAb effector functions due to the regulation of the level of expression of target Ags and responses by stimulatory incidents such as infection.


Asunto(s)
Células de la Médula Ósea/inmunología , Trasplante de Médula Ósea/inmunología , Células Asesinas Naturales/inmunología , Subfamilia A de Receptores Similares a Lectina de Células NK/inmunología , Animales , Anticuerpos Monoclonales , Citomegalovirus/inmunología , Femenino , Rechazo de Injerto/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Antígenos de Histocompatibilidad Clase I/metabolismo , Células Asesinas Naturales/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Subfamilia A de Receptores Similares a Lectina de Células NK/metabolismo , Poli I-C/farmacología
7.
Eur J Immunol ; 43(9): 2451-60, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23765421

RESUMEN

The transplantation of allergens (e.g. Phl p 5 or Bet v 1) expressed on BM cells as membrane-anchored full-length proteins leads to permanent tolerance at the T-cell, B-cell, and effector-cell levels. Since the exposure of complete allergens bears the risk of inducing anaphylaxis, we investigated here whether expression of Phl p 5 in the cytoplasm (rather than on the cell surface) is sufficient for tolerance induction. Transplantation of BALB/c BM retrovirally transduced to express Phl p 5 in the cytoplasm led to stable and durable molecular chimerism in syngeneic recipients (∼20% chimerism at 6 months). Chimeras showed allergen-specific T-cell hyporesponsiveness. Further, Phl p 5-specific TH 1-dependent humoral responses were tolerized in several chimeras. Surprisingly, Phl p 5-specific IgE and IgG1 levels were significantly reduced but still detectable in sera of chimeric mice, indicating incomplete B-cell tolerance. No Phl p 5-specific sIgM developed in cytoplasmic chimeras, which is in marked contrast to mice transplanted with BM expressing membrane-anchored Phl p 5. Thus, the expression site of the allergen substantially influences the degree and quality of tolerance achieved with molecular chimerism in IgE-mediated allergy.


Asunto(s)
Alérgenos/inmunología , Antígenos de Plantas/inmunología , Linfocitos B/inmunología , Células de la Médula Ósea/inmunología , Tolerancia Inmunológica , Proteínas de Plantas/inmunología , Células 3T3 , Alérgenos/biosíntesis , Animales , Células de la Médula Ósea/virología , Trasplante de Médula Ósea/inmunología , Línea Celular , Proliferación Celular , Quimera/inmunología , Femenino , Hipersensibilidad/inmunología , Inmunoglobulina E/sangre , Inmunoglobulina E/inmunología , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Inmunoglobulina M/sangre , Inmunoglobulina M/inmunología , Ratones , Ratones Endogámicos BALB C , Linfocitos T/inmunología , Estomatitis Vesicular/inmunología , Virus de la Estomatitis Vesicular Indiana/inmunología
8.
Eur J Immunol ; 43(9): 2327-37, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23716202

RESUMEN

Transcription factors of the Rel/NF-κB family are known to play different roles in immunity and inflammation, although the putative role of c-Rel in transplant tolerance and graft-versus-host disease (GVHD) remains elusive. We report here that T cells deficient for c-Rel have a dramatically reduced ability to cause acute GVHD after allogeneic bone marrow transplantation using major and minor histocompatibility mismatched murine models. In the study to understand the underlying mechanisms, we found that c-Rel(-/-) T cells had a reduced ability to expand in lymphoid organs and to infiltrate in GVHD target organs in allogeneic recipients. c-Rel(-/-) T cells were defective in the differentiation into Th1 cells after encountering alloantigens, but were enhanced in the differentiation toward Foxp3(+) regulatory T (Treg) cells. Furthermore, c-Rel(-/-) T cells had largely preserved activity to mediate graft-versus-leukemia response. Taken together, our findings indicate that c-Rel plays an essential role in T cells in the induction of acute GVHD, and suggest that c-Rel can be a potential target for therapeutic intervention in allogeneic hematopoietic cell transplantation in the clinic.


Asunto(s)
Trasplante de Médula Ósea/inmunología , Enfermedad Injerto contra Huésped/inmunología , Proteínas Proto-Oncogénicas c-rel/metabolismo , Linfocitos T Reguladores/inmunología , Animales , Diferenciación Celular , Proliferación Celular , Factores de Transcripción Forkhead/metabolismo , Enfermedad Injerto contra Huésped/metabolismo , Tolerancia Inmunológica/inmunología , Activación de Linfocitos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Proto-Oncogénicas c-rel/genética , Células TH1/inmunología , Células Th17/inmunología , Trasplante Homólogo
9.
J Immunol ; 190(11): 5809-17, 2013 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-23630358

RESUMEN

The effectiveness of hematopoietic stem cell transplantation as a therapy for malignant and nonmalignant conditions is complicated by pulmonary infections. Using our syngeneic bone marrow transplant (BMT) mouse model, BMT mice with a reconstituted hematopoietic system displayed increased susceptibility to Pseudomonas aeruginosa and Staphylococcus aureus. BMT alveolar macrophages (AMs) exhibited a defect in P. aeruginosa phagocytosis, whereas S. aureus uptake was surprisingly enhanced. We hypothesized that the difference in phagocytosis was due to an altered scavenger receptor (SR) profile. Interestingly, MARCO expression was decreased, whereas SR-AI/II was increased. To understand how these dysregulated SR profiles might affect macrophage function, CHO cells were transfected with SR-AI/II, and phagocytosis assays revealed that SR-AI/II was important for S. aureus uptake but not for P. aeruginosa. Conversely, AMs treated in vitro with soluble MARCO exhibited similar defects in P. aeruginosa internalization as did BMT AMs. The 3'-untranslated region of SR-AI contains a putative target region for microRNA-155 (miR-155), and miR-155 expression is decreased post-BMT. Anti-miR-155-transfected AMs exhibited an increase in SR-AI/II expression and S. aureus phagocytosis. Elevated PGE2 has been implicated in driving an impaired innate immune response post-BMT. In vitro treatment of AMs with PGE2 increased SR-AI/II and decreased MARCO and miR-155. Despite a difference in phagocytic ability, BMT AMs harbor a killing defect to both P. aeruginosa and S. aureus. Thus, our data suggest that PGE2-driven alterations in SR and miR-155 expression account for the differential phagocytosis of P. aeruginosa and S. aureus, but impaired killing ultimately confers increased susceptibility to pulmonary infection.


Asunto(s)
Dinoprostona/farmacología , Macrófagos Alveolares/efectos de los fármacos , Macrófagos Alveolares/inmunología , Fagocitosis/inmunología , Pseudomonas aeruginosa/inmunología , Receptores Depuradores/metabolismo , Staphylococcus aureus/inmunología , Animales , Trasplante de Médula Ósea/efectos adversos , Trasplante de Médula Ósea/inmunología , Regulación de la Expresión Génica/efectos de los fármacos , Macrófagos Alveolares/metabolismo , Ratones , MicroARNs/genética , MicroARNs/metabolismo , Fagocitosis/genética , Infecciones por Pseudomonas/etiología , Receptores Inmunológicos/metabolismo , Receptores Depuradores/genética , Receptores Depuradores de Clase A/genética , Receptores Depuradores de Clase A/metabolismo , Infecciones Estafilocócicas/etiología
10.
Transplantation ; 95(12): 1431-8, 2013 Jun 27.
Artículo en Inglés | MEDLINE | ID: mdl-23694950

RESUMEN

BACKGROUND: Allogeneic bone marrow transplantation is under investigation for a range of nonmalignant indications, including tolerance induction through mixed chimerism. This strategy has so far been tested experimentally only in young recipients. Due to immunosenescence, older patients have an increase in memory T cells (TMEM) as well as other alterations to their immune system, which may influence the potential to induce tolerance. We therefore investigated the impact of immunosenescence on chimerism-based tolerance induction. METHODS: Groups of young (2 months) and old (12 months) C57BL/6 recipients received BALB/c bone marrow under nonmyeloablative (3 Gy) and minimal (1 Gy) total body irradiation and treatment with costimulation blockade, T-cell depletion, or rapamycin. Multilineage chimerism, clonal deletion, and lymphocyte subsets were analyzed by flow cytometry. Tolerance was assessed by skin and heart grafts and enzyme-linked immunospot, intracellular cytokine, and mixed lymphocyte reaction assays. RESULTS: Unexpectedly, chimerism and tolerance were established in old recipients with comparable-and in some cases increased-efficacy as in young recipients employing costimulation blockade-based or T-cell depletion-based conditioning with 1 or 3 Gy total body irradiation. TMEM reactivity in (naïve) old mice was augmented in response to polyclonal but not to allogeneic stimulation, providing a mechanistic underpinning for the susceptibility to chimerism induction despite increased TMEM frequencies. Tolerance in old recipients was associated with peripheral and central clonal deletion and a higher frequency of regulatory T cells. CONCLUSION: Advanced age does not impair bone marrow engraftment, thereby widening the clinical potential of experimental protocols inducing transplantation tolerance through mixed chimerism.


Asunto(s)
Envejecimiento/inmunología , Trasplante de Médula Ósea/inmunología , Tolerancia al Trasplante/inmunología , Animales , Células de la Médula Ósea/citología , Trasplante de Médula Ósea/métodos , Citocinas/metabolismo , Femenino , Citometría de Flujo , Memoria Inmunológica , Depleción Linfocítica , Linfocitos/citología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Fenotipo , Linfocitos T/inmunología , Factores de Tiempo , Quimera por Trasplante/inmunología , Tolerancia al Trasplante/efectos de los fármacos
11.
Immunogenetics ; 65(8): 597-607, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23703256

RESUMEN

A major challenge in allogeneic bone marrow (BM) transplantation is overcoming engraftment resistance to avoid the clinical problem of graft rejection. Identifying gene pathways that regulate BM engraftment may reveal molecular targets for overcoming engraftment barriers. Previously, we developed a mouse model of BM transplantation that utilizes recipient conditioning with non-myeloablative total body irradiation (TBI). We defined TBI doses that lead to graft rejection, that conversely are permissive for engraftment, and mouse strain variation with regards to the permissive TBI dose. We now report gene expression analysis, using Agilent Mouse 8x60K microarrays, in spleens of mice conditioned with varied TBI doses for correlation to the expected engraftment phenotype. The spleens of mice given engrafting doses of TBI, compared with non-engrafting TBI doses, demonstrated substantially broader gene expression changes, significant at the multiple testing-corrected P <0.05 level and with fold change ≥2. Functional analysis revealed significant enrichment for a down-regulated canonical pathway involving B-cell development. Genes enriched in this pathway suggest that suppressing donor antigen processing and presentation may be pivotal effects conferred by TBI to enable engraftment. Regardless of TBI dose and recipient mouse strain, pervasive genomic changes related to inflammation was observed and reflected by significant enrichment for canonical pathways and association with upstream regulators. These gene expression changes suggest that macrophage and complement pathways may be targeted to overcome engraftment barriers. These exploratory results highlight gene pathways that may be important in mediating BM engraftment resistance.


Asunto(s)
Trasplante de Médula Ósea/inmunología , Regulación de la Expresión Génica , Rechazo de Injerto/genética , Irradiación Corporal Total , Animales , Linfocitos B/inmunología , Linfocitos B/metabolismo , Relación Dosis-Respuesta en la Radiación , Perfilación de la Expresión Génica/métodos , Rechazo de Injerto/inmunología , Inflamación/genética , Inflamación/patología , Ratones , Ratones Endogámicos BALB C , Análisis de Secuencia por Matrices de Oligonucleótidos , Bazo , Transcripción Genética , Quimera por Trasplante/genética , Quimera por Trasplante/inmunología , Acondicionamiento Pretrasplante/métodos , Trasplante Homólogo/inmunología
12.
Mol Immunol ; 55(3-4): 345-54, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23548836

RESUMEN

Haptoglobin (Hp), an acute phase reactant and major hemoglobin-binding protein, has a unique role in host immunity. Previously, we demonstrated that Hp-deficient C57BL/6J mice exhibit stunted development of mature T- and B-cells resulting in markedly lower levels of antigen-specific IgG. The current study identified leukocyte-derived pro-Hp as a relevant mediator of an optimal immune response. Reconstitution of Hp-/- mice with Hp+/+ bone marrow restored normal immune response to ovalbumin. Furthermore, transplanting a mixture of bone marrow-derived from B-cell-deficient and Hp-deficient mice into Rag1-/-/Hp+/+ recipients resulted in mice with a defective immune response similar to Hp-/- mice. This suggests that Hp generated by the B-cell compartment, rather than by the liver, is functionally contributing to a normal immune response. Leukocytes isolated from the spleen express Hp and release a non-proteolytically processed pro-Hp that uniquely differed from liver-derived Hp by not binding to hemoglobin. While addition of purified plasma Hp to cultured B-cells did not alter responses, pro-Hp isolated from splenocytes enhanced cellular proliferation and production of IgG. Collectively, the comparison of wild-type and Hp-deficient mice suggests a novel regulatory activity for lymphocyte-derived Hp, including Hp produced by B-cells themselves, that supports in vivo survival and functional differentiation of the B-cells to ensure an optimal immune response.


Asunto(s)
Subgrupos de Linfocitos B/citología , Subgrupos de Linfocitos B/inmunología , Células de la Médula Ósea/inmunología , Haptoglobinas/fisiología , Animales , Subgrupos de Linfocitos B/metabolismo , Células de la Médula Ósea/metabolismo , Trasplante de Médula Ósea/inmunología , Diferenciación Celular/inmunología , Supervivencia Celular/inmunología , Haptoglobinas/biosíntesis , Haptoglobinas/deficiencia , Hígado/inmunología , Hígado/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Quimera por Trasplante/inmunología
13.
PLoS One ; 8(4): e60367, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23593203

RESUMEN

Programmed cell death ligand-1 (PD-L1/CD274) is an immunomodulatory molecule involved in cancer and complications of bone marrow transplantation, such as graft rejection and graft-versus-host disease. The present study was designed to assess the dynamic expression of this molecule after hematopoietic stem cell transplantation in relation to acute graft-versus-host disease. Female BALB/c mice were conditioned with busulfan and cyclophosphamide and transplanted with either syngeneic or allogeneic (male C57BL/6 mice) bone marrow and splenic cells. The expression of PD-L1 was evaluated at different time points employing qPCR, western blot and immunohistochemistry. Allogeneic- but not syngeneic-transplanted animals exhibited a marked up-regulation of PD-L1 expression in the muscle and kidney, but not the liver, at days 5 and 7 post transplantation. In mice transplanted with allogeneic bone marrow cells, the enhanced expression of PD-L1 was associated with high serum levels of IFNγ and TNFα at corresponding intervals. Our findings demonstrate that PD-L1 is differently induced and expressed after allogeneic transplantation than it is after syngeneic transplantation, and that it is in favor of target rather than non-target organs at the early stages of acute graft-versus-host disease. This is the first study to correlate the dynamics of PD-L1 at the gene-, protein- and activity levels with the early development of acute graft-versus-host disease. Our results suggest that the higher expression of PD-L1 in the muscle and kidney (non-target tissues) plays a protective role in skeletal muscle during acute graft-versus-host disease.


Asunto(s)
Antígeno B7-H1/genética , Antígeno B7-H1/inmunología , Regulación de la Expresión Génica , Enfermedad Injerto contra Huésped/genética , Enfermedad Injerto contra Huésped/inmunología , Animales , Antígeno B7-H1/metabolismo , Trasplante de Médula Ósea/inmunología , Femenino , Perfilación de la Expresión Génica , Enfermedad Injerto contra Huésped/metabolismo , Interferón gamma/biosíntesis , Riñón/metabolismo , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Músculos/metabolismo , ARN Mensajero/genética , Acondicionamiento Pretrasplante , Trasplante Homólogo , Trasplante Isogénico , Factor de Necrosis Tumoral alfa/biosíntesis
14.
PLoS One ; 8(4): e60680, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23585844

RESUMEN

Human cells from acute myeloid leukemia (AML) patients are frequently transplanted into immune-compromised mouse strains to provide an in vivo environment for studies on the biology of the disease. Since frequencies of leukemia re-initiating cells are low and a unique cell surface phenotype that includes all tumor re-initiating activity remains unknown, the underlying mechanisms leading to limitations in the xenotransplantation assay need to be understood and overcome to obtain robust engraftment of AML-containing samples. We report here that in the NSG xenotransplantation assay, the large majority of mononucleated cells from patients with AML fail to establish a reproducible myeloid engraftment despite high donor chimerism. Instead, donor-derived cells mainly consist of polyclonal disease-unrelated expanded co-transplanted human T lymphocytes that induce xenogeneic graft versus host disease and mask the engraftment of human AML in mice. Engraftment of mainly myeloid cell types can be enforced by the prevention of T cell expansion through the depletion of lymphocytes from the graft prior transplantation.


Asunto(s)
Trasplante de Médula Ósea/patología , Enfermedad Injerto contra Huésped/patología , Leucemia Mieloide Aguda/patología , Células Mieloides/patología , Linfocitos T/patología , Trasplante Heterólogo/patología , Adulto , Anciano , Animales , Trasplante de Médula Ósea/inmunología , Trasplante de Médula Ósea/mortalidad , Proliferación Celular , Femenino , Enfermedad Injerto contra Huésped/inmunología , Humanos , Leucemia Mieloide Aguda/inmunología , Depleción Linfocítica , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Persona de Mediana Edad , Células Mieloides/inmunología , Trasplante de Neoplasias , Análisis de Supervivencia , Linfocitos T/inmunología , Quimera por Trasplante , Trasplante Heterólogo/inmunología , Trasplante Heterólogo/mortalidad , Irradiación Corporal Total
15.
Blood ; 121(21): 4303-10, 2013 May 23.
Artículo en Inglés | MEDLINE | ID: mdl-23580663

RESUMEN

Despite the use of immunosuppressive drugs, chronic allograft rejection remains a major hurdle in transplantation medicine. Induction of specific immunologic tolerance to antigens expressed by the graft would avoid its eventual functional loss and the severe side effects of paralyzing the immune system. We previously showed that donor-specific regulatory T-lymphocytes prevent rejection of fully allogeneic bone marrow (BM) grafts in mice. Thus generated hematopoietic chimeras then accepted skin and heart allografts of the same donor. We noticed that injected regulatory T-cells (Tregs) disappeared with time and investigated the mechanisms involved in the nevertheless long-term persistence of allograft tolerance. Using Tregs that can be depleted in vivo with diphtheria toxin, we show that injected cells are required for induction but not for maintenance of tolerance to BM allografts. We observed progressive deletion of donor-specific T-lymphocytes, accounting at least in part for maintenance of tolerance. Toxin-induced depletion of administered as well as host Tregs did not affect hematopoietic chimerism but it led to rapid loss of skin allografts. Therefore, our data show that newly generated host Tregs can prevent chronic allograft rejection. Long-lasting tolerance to allografts is thus achieved.


Asunto(s)
Trasplante de Médula Ósea/inmunología , Factores de Transcripción Forkhead/metabolismo , Rechazo de Injerto/inmunología , Tolerancia Inmunológica/inmunología , Trasplante de Piel/inmunología , Linfocitos T Reguladores/inmunología , Animales , Células Cultivadas , Enfermedad Crónica , Femenino , Factores de Transcripción Forkhead/inmunología , Supervivencia de Injerto/inmunología , Inmunoterapia/métodos , Masculino , Ratones , Ratones Endogámicos C57BL , Linfocitos T Reguladores/metabolismo , Linfocitos T Reguladores/trasplante , Tiempo , Quimera por Trasplante , Trasplante Homólogo
16.
Arthritis Rheum ; 65(6): 1624-35, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23508350

RESUMEN

OBJECTIVE: Sphingosine 1-phosphate (S1P) exerts a variety of activities in immune, inflammatory, and vascular systems. S1P plays an important role in systemic sclerosis (SSc) pathogenesis. Regulation of S1P in fibrotic diseases as well as in SSc was recently reported. FTY720, an oral S1P receptor modulator, has been shown to be a useful agent for the prevention of transplant rejection and autoimmune diseases. Murine sclerodermatous chronic graft-versus-host disease (GVHD) is a model for human sclerodermatous chronic GVHD and SSc. We undertook this study to investigate the effects of FTY720 in murine sclerodermatous chronic GVHD. METHODS: FTY720 was orally administered to allogeneic recipient mice from day 0 to day 20 (short-term, early-treatment group), from day 0 to day 42 (full-term, early-treatment group), or from day 22 to day 42 (delayed-treatment group) after bone marrow transplantation. RESULTS: Delayed administration of FTY720 attenuated, and early administration of FTY720 inhibited, the severity and fibrosis in murine sclerodermatous chronic GVHD. With early treatment, FTY720 induced expansion of splenic myeloid-derived suppressor cells, Treg cells, and Breg cells. Vascular damage in chronic GVHD was inhibited by FTY720 through down-regulating serum levels of S1P and soluble E-selectin. FTY720 inhibited infiltration of immune cells into skin. Moreover, FTY720 diminished the expression of messenger RNA for monocyte chemotactic protein 1, macrophage inflammatory protein 1α, RANTES, tumor necrosis factor α, interferon-γ, interleukin-6 (IL-6), IL-10, IL-17A, and transforming growth factor ß1 in the skin. CONCLUSION: FTY720 suppressed the immune response by promoting the expansion of regulatory cells and reducing vascular damage and infiltration of immune cells into the skin. Taken together, these results have important implications for the potential use of FTY720 in the treatment of sclerodermatous chronic GVHD and SSc in humans.


Asunto(s)
Trasplante de Médula Ósea/inmunología , Citocinas/metabolismo , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Inmunosupresores/uso terapéutico , Fosfohidrolasa PTEN/metabolismo , Glicoles de Propileno/uso terapéutico , Esclerodermia Localizada/tratamiento farmacológico , Piel/inmunología , Esfingosina/análogos & derivados , Bazo/inmunología , Animales , Ensayo de Inmunoadsorción Enzimática , Femenino , Clorhidrato de Fingolimod , Citometría de Flujo , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/patología , Inmunohistoquímica , Masculino , Ratones , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Esclerodermia Localizada/inmunología , Esclerodermia Localizada/patología , Piel/patología , Esfingosina/uso terapéutico
17.
Blood ; 121(20): 4231-41, 2013 May 16.
Artículo en Inglés | MEDLINE | ID: mdl-23520337

RESUMEN

The graft-versus-tumor (GVT) effect after allogeneic hematopoietic cell transplantation (allo-HCT) represents an effective form of immunotherapy against many malignancies. Meaningful separation of the potentially curative GVT responses from graft-versus-host disease (GVHD), the most serious toxicity following T-cell replete allo-HCT, has been an elusive goal. GVHD is initiated by alloantigens, although both alloantigens and tumor-specific antigens (TSAs) initiate GVT responses. Emerging data have illuminated a role for antigen-presenting cells (APCs) in inducing alloantigen-specific responses. By using multiple clinically relevant murine models, we show that a specific subset of host-derived APCs-CD8(+) dendritic cells (DCs)-enhances TSA responses and is required for optimal induction of GVT. Stimulation of TLR3, which among host hematopoietic APC subsets is predominantly expressed on CD8(+) DCs, enhanced GVT without exacerbating GVHD. Thus, strategies that modulate host APC subsets without direct manipulation of donor T cells could augment GVT responses and enhance the efficacy of allo-HCT.


Asunto(s)
Trasplante de Médula Ósea/inmunología , Trasplante de Médula Ósea/fisiología , Células Dendríticas/fisiología , Efecto Injerto vs Tumor/inmunología , Animales , Antígenos CD8/metabolismo , Células Cultivadas , Células Dendríticas/metabolismo , Femenino , Efecto Injerto vs Tumor/fisiología , Leucemia/inmunología , Leucemia/terapia , Linfoma/inmunología , Linfoma/terapia , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , Donantes de Tejidos , Trasplante Homólogo , Regulación hacia Arriba/inmunología
18.
Br J Cancer ; 108(5): 1092-9, 2013 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-23511628

RESUMEN

BACKGROUND: Perspectives of immunotherapy to cancer mediated by bone marrow transplantation (BMT) in conjunction with dendritic cell (DC)-mediated immune sensitisation have yielded modest success so far. In this study, we assessed the impact of DC on graft vs tumour (GvT) reactions triggered by allogeneic BMT. METHODS: H2K(a) mice implanted with congenic subcutaneous Neuro-2a neuroblastoma (NB, H2K(a)) tumours were irradiated and grafted with allogeneic H2K(b) bone marrow cells (BMC) followed by immunisation with tumour-inexperienced or tumour-pulsed DC. RESULTS: Immunisation with tumour-pulsed donor DC after allogeneic BMT suppressed tumour growth through induction of T cell-mediated NB cell lysis. Early post-transplant administration of DC was more effective than delayed immunisation, with similar efficacy of DC inoculated into the tumour and intravenously. In addition, tumour inexperienced DC were equally effective as tumour-pulsed DC in suppression of tumour growth. Immunisation of DC did not impact quantitative immune reconstitution, however, it enhanced T-cell maturation as evident from interferon-γ (IFN-γ) secretion, proliferation in response to mitogenic stimulation and tumour cell lysis in vitro. Dendritic cells potentiate GvT reactivity both through activation of T cells and specific sensitisation against tumour antigens. We found that during pulsing with tumour lysate DC also elaborate a factor that selectively inhibits lymphocyte proliferation, which is however abolished by humoral and DC-mediated lymphocyte activation. CONCLUSION: These data reveal complex involvement of antigen-presenting cells in GvT reactions, suggesting that the limited success in clinical application is not a result of limited efficacy but suboptimal implementation. Although DC can amplify soluble signals from NB lysates that inhibit lymphocyte proliferation, early administration of DC is a dominant factor in suppression of tumour growth.


Asunto(s)
Trasplante de Médula Ósea/inmunología , Células Dendríticas/trasplante , Efecto Injerto vs Tumor/inmunología , Neuroblastoma/terapia , Animales , Células Presentadoras de Antígenos/inmunología , Inmunización Pasiva , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Neuroblastoma/inmunología , Linfocitos T Citotóxicos/inmunología , Trasplante Homólogo
19.
J Immunol ; 190(9): 4525-34, 2013 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-23530149

RESUMEN

A mutation in the IL7Rα locus has been identified as a risk factor for multiple sclerosis (MS), a neurodegenerative autoimmune disease characterized by inflammation, demyelination, and axonal damage. IL7Rα has well documented roles in lymphocyte development and homeostasis, but its involvement in disease is largely understudied. In this study, we use the experimental autoimmune encephalomyelitis (EAE) model of MS to show that a less severe form of the disease results when IL7Rα expression is largely restricted to thymic tissue in IL7RTg(IL7R-/-) mice. Compared with wild-type (WT) mice, IL7RTg(IL7R-/-) mice exhibited reduced paralysis and myelin damage that correlated with dampened effector responses, namely decreased TNF production. Furthermore, treatment of diseased WT mice with neutralizing anti-IL7Rα Ab also resulted in significant improvement of EAE. In addition, chimeric mice were generated by bone marrow transplant to limit expression of IL7Rα to cells of either hematopoietic or nonhematopoietic origin. Mice lacking IL7Rα only on hematopoietic cells develop severe EAE, suggesting that IL7Rα expression in the nonhematopoietic compartment contributes to disease. Moreover, novel IL7Rα expression was identified on astrocytes and oligodendrocytes endogenous to the CNS. Chimeric mice that lack IL7Rα only on nonhematopoietic cells also develop severe EAE, which further supports the role of IL7Rα in T cell effector function. Conversely, mice that lack IL7Rα throughout both compartments are dramatically protected from disease. Taken together, these data indicate that multiple cell types use IL7Rα signaling in the development of EAE, and inhibition of this pathway should be considered as a new therapeutic avenue for MS.


Asunto(s)
Encefalomielitis Autoinmune Experimental/inmunología , Activación de Linfocitos/inmunología , Receptores de Interleucina-7/inmunología , Linfocitos T/inmunología , Animales , Astrocitos/inmunología , Trasplante de Médula Ósea/inmunología , Linaje de la Célula , Sistema Nervioso Central/inmunología , Citocinas/inmunología , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Esclerosis Múltiple/inmunología , Mutación/inmunología , Vaina de Mielina/inmunología , Oligodendroglía/inmunología , Timo/inmunología , Factor de Necrosis Tumoral alfa/inmunología
20.
Blood ; 121(16): 3274-83, 2013 Apr 18.
Artículo en Inglés | MEDLINE | ID: mdl-23422748

RESUMEN

Chronic graft-versus-host disease (cGVHD) is an increasingly frequent cause of morbidity and mortality of allogeneic hematopoietic stem-cell transplantation. Sclerodermatous cGVHD (Scl-cGVHD) is characterized by fibrosis and autoimmune features resembling those of systemic sclerosis (SSc). Transplantation of B10.D2 bone marrow and splenocytes into irradiated BALB/c mice is an established model of human Scl-cGVHD. To examine the role of B cells in Scl-cGVHD, CD19-deficient (CD19(-/-)) mice were used as donors or recipients. CD19(-/-) donors induced more severe Scl-cGVHD than wild-type donors, but use of CD19(-/-) recipients resulted in no significant differences compared with wild-type recipients. Moreover, CD19 deficiency on donor B cells resulted in the expansion of splenic interleukin (IL) -6-producing monocytes/macrophages, cytotoxic CD8(+) T cells, and Th1 cells during the early stage of disease and increased the infiltration of T cells, TGF-ß-producing monocytes/macrophages, and Th2 cells into the skin in the later stage of Scl-cGVHD. IL-10-producing regulatory B cells (B10 cells) were not reconstituted by CD19(-/-) donor cells, and early adoptive transfer of B10 cells attenuated the augmented manifestations of CD19(-/-) donor-induced Scl-cGVHD. Therefore, donor-derived B10 cells have a suppressive role in Scl-cGVHD development, warranting future investigation of regulatory B-cell-based therapy for treatment of Scl-cGVHD and SSc.


Asunto(s)
Linfocitos B Reguladores/inmunología , Trasplante de Médula Ósea/inmunología , Enfermedad Injerto contra Huésped/inmunología , Esclerodermia Sistémica/inmunología , Piel/inmunología , Traslado Adoptivo , Animales , Antígenos CD19/genética , Antígenos CD19/inmunología , Antígenos CD1d/análisis , Antígenos CD1d/inmunología , Trasplante de Médula Ósea/efectos adversos , Antígeno CD11b/análisis , Antígeno CD11b/inmunología , Antígenos CD5/análisis , Antígenos CD5/inmunología , Enfermedad Crónica , Femenino , Fibrosis/inmunología , Fibrosis/patología , Eliminación de Gen , Enfermedad Injerto contra Huésped/patología , Humanos , Interleucina-6/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Monocitos/inmunología , Esclerodermia Sistémica/patología , Piel/patología , Linfocitos T/inmunología
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