PRECLINICAL GVHD AND MARROW ENGRAFTMENT STUDIES

描述：(申请人描述)移植物抗宿主病(GvHD)是异基因骨髓移植(BMT)的主要并发症。骨髓供受者的HLA配型可以降低GvHD的风险，配型匹配的兄弟姐妹是首要选择。然而，只有大约30%的患者有HLA相合的同胞，因此必须通过国家骨髓捐赠者计划(NMDP)寻找合适的非血缘关系相合的捐赠者。在无血缘关系的人类白细胞抗原相合的患者中，GvHD的风险仍然相当高，特别是由于MHC II类基因座的遗传变异，其产品可以诱导CD4+T细胞反应。骨髓移植排斥反应的预防也是异基因骨髓移植的一个关键问题，特别是当涉及MHC II类错配时。作为该计划的一部分，我们将注意力集中在基于结构设计的多肽和有机化合物的临床前研究上，这些多肽和有机化合物可以抑制CD4+T细胞介导的同种异体反应。我们将集中精力在三组抑制剂上：(1)D1CC‘环肽(802-2)，当前临床试验的先导化合物；(2)设计用于抑制D4结构域中CD4分子二聚的新肽；以及(3)两种有机化合物(TJU103和TJU104)，它们被选为能够阻断D1域上假定的结合口袋。我们将使用的骨髓移植模型包括：(1)MHC半相合的B6D2-和GT；B6CB(950cGy)和次要组织相容性抗原(HA)不匹配的B6-和GT；BALB.B(850cGy)GvHD模型；以及2)MHC半相合的B6CB ATBM-和GT；B6D2(750cGy)，MHC II类不同的Bm12 ATBM-和GT；BLy6.5.2(700cGy)，以及CD4-II限制的微小HA不同的BALB.B ATBM&GT；B6(700cGy)预敏异基因骨髓移植排斥反应模型。根据这些模型中选择的多肽和化合物，我们的具体目的是：1)确定802-2、CD4D4和有机抑制剂在GvHD和骨髓移植排斥反应模型中的有效性；(2)确定抑制剂的作用机制；(3)评估骨髓移植受者在GvHD模型中接受抑制药物治疗后的免疫活性状态。这些研究将为这些新型的CD4抑制剂提供强有力的临床前基础，这些抑制剂可以潜在地靶向同种异体反应细胞，而不会危及后来对感染和白血病的免疫反应。

DESCRIPTION: (Applicant's Description) Graft-versus-host disease (GvHD) is a major complication of allogeneic bone marrow transplantation (BMT). The risk of GvHD can be reduced by HLA-matching of the marrow donor and recipient, with a matched sibling being the primary choice. Yet, only about 30% of patients have a HLA-matched sibling, and thus must seek suitable unrelated HLA-matched donors through the National Marrow Donor Program (NMDP). The risk of GvHD is still quite high in unrelated HLA-matched patients, particularly due to genetic variants in MHC class II loci, whose products can induce CD4+ T cell responses. The prevention of marrow graft rejection is also a critical issue for allogeneic BMT, particularly when involving MHC class II mismatches. As part of this Program, we have focused our attention on the preclinical investigation of structure-base designed peptides and organic compounds that inhibit CD4+ T cell-mediated alloreactivity. We will concentrate our efforts on three groups of inhibitors: (1) the D1 CC' loop peptide (802-2), the lead compound for the current clinical trial; (2) new peptides designed to inhibit dimerization of CD4 molecules in the D4 domain; and (3) two organic compounds (TJU103, and TJU104) that were selected for their ability to block a putative binding pocket on the D1 domain. The BMT models that we will utilize include: (1) the MHC haploidentical B6D2->B6CB (950 cGy) and minor histocompatibility antigen (HA)-mismatched B6 ->BALB.B (850 cGy) models of GvHD; and 2) the MHC haploidentical B6CB ATBM->B6D2 (750 cGy), MHC Class II-disparate Bm12 ATBM->B6.Ly5.2 (700 cGy), and the CD4-Class II-restricted minor HA-disparate BALB.B ATBM->B6 (700 cGy) presensitized models of allogeneic marrow graft rejection. With the selected peptides and compounds in these models, our specific aims are: 1) to determine the efficacy of the 802-2, CD4 D4, and organic inhibitory agents in the GvHD and marrow graft rejection models; (2) to determine mechanism of action of the inhibitory agents; and (3) to evaluate the immunocompetent status of BMT recipients in the GvHD models after treatment with the inhibitory agents. These studies will provide a strong preclinical basis for these novel CD4 inhibitors that could potentially target alloreactive cells without jeopardizing later immune responses to infection and leukemia.