罕见开米拉A_3B_3血型的分子生物学研究

目的一例ABO表型鉴定困难的个体及其家系的分子遗传背景的研究。方法用常规血清血型方法,对其ABO血型分型;PCR-SSP法进行基因分型;同时通过ABO基因直接测序及克隆测序、HLA分型、以及15个常染色体位点短串联重复序列检测对该研究对象进行家系研究。结果患者血清学分型定为A3B3型,其ABO基因分型、序列测定、HLA-B、DR基因分型、和STR-PCR特异性检测的vWA和D8S1179位点均有两个以上的单倍体存在。结论该研究对象认定是一例罕见的开米拉血型,清晰提示此罕见血型的分子基础,有助于深入认识此种分子遗传的方式。     

IL-2 pathway blocking in combination with anti-CD154 synergistically establishes mixed macrochimerism with limited dose of bone marrow cells and prolongs skin graft survival in mice

To facilitate the establishment of mixed chimerism with limited dose of bone marrow (BM) cells, and to achieve tolerance in skin graft model, combined blocking of costimulatory pathway and IL-2 pathway was used in minimally myeloablative model using busulfan. BM cells (2.5x10(7)) of BALB/c were injected into C57BL/6 mice at day 0 with full thickness skin graft after single dose injection of busulfan (25 mg/kg) on day-1. Recipients were grouped and injected the anti-CD154, CTLA4-Ig, anti-IL-2R at days 0, 2, 4, and 6 according to protocol. Mixed macrochimerism were induced in groups treated with anti-CD154+anti-CTLA4-Ig, anti-CD154+anti-IL-2R, and anti-CD154+anti-CTLA4 Ig+anti-IL-2R. Three groups having chimerism enjoyed prolonged graft survival more than 6 months. Superantigen deletion study revealed deletion of alloreactive T cells in combined blockade treated groups. In graft versus host disease model using CFSE staining, CD4+ T cell and CD8+ T cell proliferation were reduced in groups treated with CTLA4-Ig or anti-IL-2R or both in combination with anti-CD154. However, anti-IL-2R was not so strong as CTLA4-Ig in terms of inhibition of T cell proliferation. In conclusion, IL-2 pathway blocking combined with anti-CD154 can establish macrochimerism with limited dose of BM transplantation and induce specific tolerance to allograft.     

Hematopoietic stem cell transplantation with latently infected donors does not transmit virus to immunocompromised recipients in the murine model of cytomegalovirus infection

Hematopoietic stem cell transplantation (HSCT) bears a risk of reactivating latent cytomegalovirus (CMV) in either the transplanted hematopoietic donor cells or in parenchymal and stromal tissue cells of the immunocompromised recipient, or in both. While reactivated human CMV in recipients of organ transplantations is frequently the virus variant of the donor, this is not usually the case in HSCT recipients. Here we have used experimental sex-mismatched HSCT in the BALB/c mouse model to test if latent murine CMV from CMV-immune donors is transmitted with bone marrow cells to naive immunocompromised recipients.     

A novel IL2RG mutation associated with maternal T lymphocyte engraftment in a patient with severe combined immunodeficiency

Severe combined immunodeficiency (SCID) represents a genetically heterogeneous group of primary immunodeficiency disorders. Irrespective of the genetic defect, patients with SCID may be engrafted with transplacentally derived maternal T-lymphocytes that in a subset of cases may be responsive to phytohemagglutinin. Here, we present, from a genetic perspective, an SCID patient who not only harbored a novel mutation in the gene encoding the common chain (c) of the IL-2 receptor (IL2RG), but also carried reactive maternal T lymphocytes that produced a karyotype that was initially perplexing.     

Vascularized Osteomyocutaneous Allografts Are Permissive to Tolerance by Induction‐Based Immunomodulatory Therapy

Vascularized composite allografts (VCAs) are unique among transplanted organs in that they are composed of multiple tissues with disparate antigenic and immunologic properties. As the predominant indications for VCAs are non‐life‐threatening conditions, there is an immediate need to develop tolerance induction strategies and to elucidate the mechanisms of VCA rejection and tolerance using VCA‐specific animal models. In this study, we explore the effects of in vitro induced donor antigen‐specific CD4^?CD8^? double negative (DN) Treg‐based therapy, in a fully MHC mismatched mouse VCA such as a vascularized osteomyocutaneous as compared to a non‐VCA such as a full thickness skin (FTS) transplantation model to elucidate the unique features of VCA rejection and tolerance. We demonstrate that combined therapy with antigen‐induced CD4 derived DN Tregs and a short course of anti‐lymphocyte serum, rapamycin and IL‐2/Fc fusion protein results in donor‐specific tolerance to VCA, but not FTS allografts. Macrochimerism was detected in VCA but not FTS allograft recipients up to >60 days after transplantation. Moreover, a significant increase of CD4⁺Foxp3⁺ Tregs was found in the peripheral blood of tolerant VCA recipients. These data suggest that VCA are permissive to tolerance induced by DN Treg‐based induction therapy.

     

人干细胞实验动物嵌合体模型的研究进展

动物模型是疾病研究、发病机制、药物治疗的必要工具,目前一些困扰人类健康的重大疾病如艾滋病、乙型肝炎等因为还没有能反映人类疾病发病机理的理想动物模型。人干细胞是能在体外长期培养的、高度未分化的全能细胞系,亚全能细胞系和分化的干细胞等。如果能将人的干细胞成功移植入实验动物体内形成人源化嵌合体动物,有希望为艾滋病、肝炎等的研究制备适当的模型。人类干细胞在动物中的移植研究中主要的实验动物是绵羊,小鼠等,本文介绍了人干细胞在动物体内移植的研究进展。     

肝细胞移植嵌合体动物模型研究进展

乙型肝炎病毒的研究主要涉及病毒的感染、致病机制和药物筛选评价等方面,病毒感染有高度的种属性和组织特异性,病毒黏附以及病毒DNA转录、复制对细胞有着严格的要求,建立经济有效的动物模型是研究的关键。肝细胞移植嵌合体动物模型可为研究提供新的技术手段,具有良好的前景与发展意义。本文主要介绍了集中肝嵌合体动物模型的研究进展,探讨了嵌合体模型构造方法、移植肝细胞增殖等情况。     

肝移植移植物抗宿主病的嵌合体检测及意义

肝移植移植物抗宿主病（GVHD）是一罕见并发症，发病率约占1％。1994-2002年行原位肝移植（OLT）的23452例患者中19例发生GVHD。GVHD通常发生在肝移植术后2～8周，病程急、病情凶险。典型临床表现为发热、皮疹、腹泻、全血细胞减少。但也有例外，Kuball等报道1例50岁女性原发性胆汁性肝硬化患者，接受32岁HLA纯合型儿子的肝脏，术后114d发生GVHD。2003年全球发生4例慢性GVHD。[第一段]