RESUMO
PURPOSE OF REVIEW: Antibody-mediated rejection (AMR) is emerging as the leading cause of chronic rejection and allograft failure. Traditionally, the mechanisms of graft injury mediated by donor-specific antibodies beyond complement activation were not well appreciated. However, an evolving paradigm of Fc-independent antibody functions, along with clinical recognition of C4d-negative AMR, has increased awareness of the action of antibodies leading to endothelial activation and dysfunction. RECENT FINDINGS: Herein, we address current clinical trends, including the signature of microvascular inflammation in biopsies of grafts undergoing AMR, the prevalence of antibodies to human leukocyte antigen class II DQ locus (HLA-DQ) and non-HLA targets, and the functional characterization of HLA immunoglobulin G (IgG) subclasses and complement-fixing capacity. We also discuss recent experimental evidence revealing new mechanisms of endothelial and smooth muscle cell activation by HLA antibodies, which may contribute to vascular inflammation and chronic rejection. Finally, we touch upon novel discoveries of the interplay between antibodies, the complement system, and CD4 T-cell-mediated alloimmunity. SUMMARY: The current literature suggests that, although complement-fixing antibodies may have some prognostic value for graft outcome, complement-independent mechanisms of graft injury are increasingly relevant. Therapeutic strategies, which target endothelial activation induced by antibodies may ameliorate vascular inflammation and mononuclear cell infiltration characteristic of AMR.
Assuntos
Anticorpos/imunologia , Proteínas do Sistema Complemento/imunologia , Rejeição de Enxerto/imunologia , Antígenos HLA-DQ/imunologia , Humanos , Imunoglobulina G/imunologia , Doadores de Tecidos , Imunologia de TransplantesRESUMO
The role of CD8(+) T cells in the pathogenesis of asthma remains controversial, as both pro- and anti-inflammatory functions have been suggested. This study was designed to examine the endogenous CD8(+) T cell response in a biphasic ovalbumin (OVA)-induced model of allergic airway disease (AAD) and its subsequent resolution with the development of local inhalational tolerance (LIT). We observed increases in OVA-specific CD8(+) T cell numbers in the local lung compartments (bronchoalveolar lavage, lung tissue, hilar lymph node) at AAD and LIT; systemic compartments (spleen, inguinal lymph node) displayed no such increases in CD8(+) T cell numbers. OVA-specific CD8(+) T cells appeared to exhibit plasticity both phenotypically and functionally. They possessed pro-inflammatory characteristics at AAD, with high phenotypic expression of CD11a and increased functional expression of granzyme B and interferon-γ. In contrast, at LIT they showed increased phenotypic expression of the inhibitory marker NKG2A and functionally did not produce granzyme B or interferon-γ. In addition, in a discontinuous model the OVA-specific CD8(+) T cells could be recalled on re-exposure to OVA, demonstrating memory. Finally, confocal microscopy results showed that OVA-specific CD8(+) T cells at AAD are associated with B cell aggregates in lung tissue. These B cell aggregates resembled tertiary ectopic lymphoid tissue and may thus provide a local environment for the salient cellular interactions that contribute to the development of LIT.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Hipersensibilidade Respiratória/imunologia , Administração por Inalação , Animais , Linfócitos B/imunologia , Brônquios/imunologia , Líquido da Lavagem Broncoalveolar/imunologia , Agregação Celular/imunologia , Feminino , Granzimas/metabolismo , Tolerância Imunológica , Memória Imunológica , Imunofenotipagem , Interferon gama/metabolismo , Pulmão/imunologia , Linfonodos/imunologia , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Confocal , Subfamília C de Receptores Semelhantes a Lectina de Células NK/análise , Ovalbumina/administração & dosagem , Ovalbumina/imunologia , Linfócitos T Reguladores/imunologiaRESUMO
Although functional asplenia from infarctions may be a major contributor to increased infectious mortality in sickle-cell disease (SCD), this relationship has not been fully defined. We used the transgenic Berkeley SCD mouse to define blood and splenic immunophenotypic differences in this model compared with C57BL/6 and hemizygous controls. In the serum of SCD mice, we found increased IgG2a and suppressed IgM, IgG2b, and IgA levels. Serum IL-6 levels in SCD mice were elevated, whereas IL-1α, CXCL10, and CCL5 levels were decreased. The blood of SCD mice had higher white blood cell counts, with an increased percentage of lymphocytes and decreases in other leukocytes. Immunophenotyping of lymphocytes revealed higher percentages of CD8(+) and T-regulatory cells and lower percentages of B cells. SCD mouse spleens exhibited histological disorganization, with reduction of defined lymphoid follicles and expansion of red pulp, a greater than fourfold increase in splenic mononuclear cells, marked expansion of the nucleated red blood cell fraction, and B-cell and CD8(+) T-cell lymphopenia. Within the splenic B-cell population, there was a significant decrease in B-1a B cells, with a corresponding decrease in IgA secreting plasma cells in the gut. Confocal microscopy of spleens demonstrated complete disruption of the normal lymphofollicular structure in the white pulp of SCD mice without distinct B, T, and marginal zones. Our findings suggest that altered SCD splenic morphological characteristics result in an impaired systemic immune response.
Assuntos
Anemia Falciforme/imunologia , Anemia Falciforme/patologia , Imunidade/imunologia , Baço/imunologia , Baço/patologia , Anemia Falciforme/sangue , Anemia Falciforme/complicações , Animais , Linfócitos B/imunologia , Quimiocinas/sangue , Modelos Animais de Doenças , Feminino , Hemizigoto , Imunoglobulinas/sangue , Interleucina-1alfa/sangue , Interleucina-6/sangue , Contagem de Leucócitos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia Confocal , Soro , Linfócitos T/imunologiaRESUMO
Due to redundancy with other tyrosine phosphatases, the ubiquitously expressed tyrosine phosphatase SHP-2 (encoded by Ptpn11) is not required for T cell development. However, Ptpn11 gene deletion driven by CD4 Cre recombinase leads to cartilage tumors in the wrist. Using a fate mapping system, we demonstrate that wrist tumor development correlates with increased frequency and numbers of non-hematopoietic lineage negative CD45 negative cells with a bone chondrocyte stromal cell precursor cell (BCSP) phenotype. Importantly, the BCSP subset has a history of CD4 expression and a marked wrist location tropism, explaining why the wrist is the main site of tumor development. Mechanistically, we found that in SHP-2 absence, SOX-9 is no longer regulated, leading to an uncontrolled proliferation of the BCSP subset. Altogether, these results identify a unique subset of chondrocyte precursors tightly regulated by SHP-2. These findings underscore the need for the development of methods to therapeutically target this subset of cells, which could potentially have an impact on treatment of SHP-2 dysfunction linked debilitating diseases.
Assuntos
Neoplasias Ósseas , Condrócitos , Proteína Tirosina Fosfatase não Receptora Tipo 11 , Punho/patologia , Animais , Neoplasias Ósseas/etiologia , Neoplasias Ósseas/patologia , Antígenos CD4/metabolismo , Cartilagem/patologia , Diferenciação Celular/genética , Condrócitos/metabolismo , Condrócitos/patologia , Humanos , Camundongos , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Linfócitos T/metabolismoRESUMO
Comorbid asthma in sickle cell disease (SCD) confers higher rates of vaso-occlusive pain and mortality, yet the physiological link between these two distinct diseases remains puzzling. We used a mouse model of SCD to study pulmonary immunology and physiology before and after the induction of allergic airway disease (AAD). SCD mice were sensitized with ovalbumin (OVA) and aluminum hydroxide by the intraperitoneal route followed by daily, nose-only OVA-aerosol challenge to induce AAD. The lungs of naive SCD mice showed signs of inflammatory and immune processes: (1) histologic and cytochemical evidence of airway inflammation compared with naive wild-type mice; (2) bronchoalveolar lavage (BAL) fluid contained increased total lymphocytes, %CD8+ T cells, granulocyte-colony stimulating factor, interleukin 5 (IL-5), IL-7, and chemokine (C-X-C motif) ligand (CXCL)1; and (3) lung tissue and hilar lymph node (HLN) had increased CD4+, CD8+, and regulatory T (Treg) cells. Furthermore, SCD mice at AAD demonstrated significant changes compared with the naive state: (1) BAL fluid with increased %CD4+ T cells and Treg cells, lower %CD8+ T cells, and decreased interferon gamma, CXCL10, chemokine (C-C motif) ligand 2, and IL-17; (2) serum with increased OVA-specific immunoglobulin E, IL-6, and IL-13, and decreased IL-1α and CXCL10; (3) no increase in Treg cells in the lung tissue or HLN; and (4) hyporesponsiveness to methacholine challenge. In conclusion, SCD mice have an altered immunologic pulmonary milieu and physiological responsiveness. These findings suggest that the clinical phenotype of AAD in SCD mice differs from that of wild-type mice and that individuals with SCD may also have a unique, divergent phenotype perhaps amenable to a different therapeutic approach.
Assuntos
Anemia Falciforme/complicações , Anemia Falciforme/imunologia , Hipersensibilidade/complicações , Hipersensibilidade/imunologia , Inflamação/complicações , Inflamação/imunologia , Pulmão/patologia , Anemia Falciforme/sangue , Animais , Asma/sangue , Asma/complicações , Asma/imunologia , Hiper-Reatividade Brônquica/sangue , Hiper-Reatividade Brônquica/complicações , Hiper-Reatividade Brônquica/imunologia , Líquido da Lavagem Broncoalveolar , Citocinas/sangue , Modelos Animais de Doenças , Eosinófilos/metabolismo , Feminino , Hemizigoto , Hipersensibilidade/sangue , Inflamação/sangue , Contagem de Leucócitos , Pulmão/imunologia , Camundongos Endogâmicos C57BL , Muco/metabolismo , Ovalbumina/imunologia , Linfócitos T/imunologiaRESUMO
The incidence of atopic conditions has increased in industrialized countries. Persisting symptoms and concern for drug side-effects lead patients toward adjunctive treatments such as phytotherapy. Previously, we have shown that Bromelain (sBr), a mixture of cysteine proteases from pineapple, Ananas comosus, inhibits ovalbumin (OVA)-induced murine model of allergic airway disease (AAD). However, sBr's effect on development of AAD when treatment is administered throughout OVA-alum sensitization was unknown and is the aim of the present study. C57BL/6J mice were sensitized with OVA/alum and challenged with 7 days OVA aerosol. sBr 6 mg/kg/0.5 ml or PBS vehicle were administered throughout sensitization. Lung, bronchoalveolar lavage (BAL), spleen, and lymph nodes were processed for flow cytometry and OVA-specific IgE was determined via ELISA. sBr treatment throughout OVA-alum sensitization significantly reduced the development of AAD (BAL eosinophils and lymphocytes). OVA-specific IgE and OVA TET(+) cells were decreased. sBr reduced CD11c(+) dendritic cell subsets, and in vitro treatment of DCs significantly reduced CD44, a key receptor in both cell trafficking and activation. sBr was shown to reduce allergic sensitization and the generation of AAD upon antigen challenge. These results provide additional insight into sBr's anti-inflammatory and antiallergic properties and rationale for translation into the clinical arena.