RESUMO
The importance of the human leukocyte antigen (HLA) system in kidney transplantation is well-known, but it remains unexplored if patient HLA antigens constitute independent risk factors in complications after transplantation. We hypothesized that specific HLA class II phenotypes associated with immune-mediated disease (HLA-IMD) predispose to immunological activity and/or complications after kidney transplantation. Based on the literature we defined HLA-DR2-DQ6; -DR3-DQ2 and -DR4-DQ8 as HLA-IMD phenotypes. We investigated associations between HLA-IMD phenotypes in patients, biomarkers of systemic chronic inflammation at the time of transplantation, and the outcome after kidney transplantation in a retrospective cohort study of 611 kidney transplanted patients. The HLA-IMD phenotypes were associated with higher levels of biomarkers of systemic inflammation. The HLA-DR4-DQ8 phenotype was associated with mortality after transplantation in Cox analyses with adjustments for confounders. Data support the hypothesis that specific HLA class II phenotypes affects immunological pathways that determine the midterm clinical outcome of kidney transplantation.
Assuntos
Antígenos HLA/genética , Antígeno HLA-DR4/genética , Transplante de Rim/mortalidade , Adulto , Biomarcadores/metabolismo , Feminino , Genótipo , Humanos , Inflamação/genética , Inflamação/mortalidade , Masculino , Pessoa de Meia-Idade , Fenótipo , Estudos RetrospectivosRESUMO
HLA-C*07:780 differs from HLA-C*07:04:01:01 in exon 2 at amino acid 49; alanine to threonine substitution.
Assuntos
Genes MHC Classe I , Antígenos HLA-C , Alelos , Substituição de Aminoácidos , Dinamarca , Feminino , Antígenos HLA-C/genética , Humanos , Análise de Sequência de DNARESUMO
Purpose: Targeting the B-cell receptor (BCR) pathway with inhibitors of Bruton tyrosine kinase (BTK) and PI3Kδ is highly effective for the treatment of chronic lymphocytic leukemia (CLL). However, deep remissions are uncommon, and drug resistance with single-agent therapy can occur. In vitro studies support the effectiveness of combing PI3Kδ and BTK inhibitors.Experimental Design: As CLL proliferation and survival depends on the microenvironment, we used murine models to assess the efficacy of the BTK inhibitor acalabrutinib combined with the PI3Kδ inhibitor ACP-319 in vivo We compared single-agent with combination therapy in TCL1-192 cell-injected mice, a model of aggressive CLL.Results: We found significantly larger reductions in tumor burden in the peripheral blood and spleen of combination-treated mice. Although single-agent therapy improved survival compared with control mice by a few days, combination therapy extended survival by over 2 weeks compared with either single agent. The combination reduced tumor proliferation, NF-κB signaling, and expression of BCL-xL and MCL-1 more potently than single-agent therapy.Conclusions: The combination of acalabrutinib and ACP-319 was superior to single-agent treatment in a murine CLL model, warranting further investigation of this combination in clinical studies. Clin Cancer Res; 23(19); 5814-23. ©2017 AACR.