Immune Therapy For Cytomegalovirus Infection

巨细胞病毒感染的免疫治疗

• 批准号: 7215771
• 负责人: David Frank Stroncek
• 金额: --
• 依托单位: CLINICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7215771
• 关键词: Herpesviridae disease; cellular immunity; cytomegalovirus; cytotoxic T lymphocyte; epitope mapping; hematopoietic tissue transplantation; histocompatibility antigens; human subject; immunologic substance development /preparation; immunotherapy; leukocyte activation /transformation; patient oriented research; peptide library; protein structure; stem cell transplantation; transplantation disease transmission; transplantation immunology; virus antigen

Cytomegalovirus (CMV) infections remain a serious problem in hematopoietic stem cell transplant patients. Following transplantation CMV infections can cause peumonititis, hepatitis, enteritis, and marrow failure. CMV seropositive transplant recipients can be treated with antiviral agents such as ganciclovir at the onset of infection or at the time of stem cell engraftment, but ganciclovir therapy is associated with renal toxicity and suppression of neutrophil counts. Preliminary studies have found that adoptive immune therapy using CMV-reactive cytotoxic T lymphocytes (CTL) is an effective and less toxic alternative to prevention of CMV infection in transplant recipeints. The purpose of this study is to develop new treatment strategies for producing CMV-reactive CTLs that can be used for adoptive immunetherapy and to better understand the cellular immune response to CMV. Current studies are focused on identifying the immune dominant peptides that can be used to stimulate CMV reactive CTLs. CMV contains over 200 proteins, but two proteins CMV proteins pp65 and IE1, have been found to be immune dominant. We found that the peptide CMV pp65 91-100 was found an immune dominant peptide restricted to HLA-A*33 and pp65 328-337 was an immune dominant peptide restricted to HLA-A*2402. We are now using libraries of pp65 and IE1 overlapping peptides of 15 amino acids in length to identify new class I and class II epitopes. Class I and class II epitopes have been found among both the pp65 and IE1 peptides. To further characterize the class I eptitopes, the 9 amino acid peptides that made up the reactive 15 amino acid peptides were tested for reactivity toward CD8 cells. Several pp65 and IE1 reactive peptides 9 amino acids in length have been identified. Future studies will characterize the HLA restrictions of the class I and class II epitopes.

在造血干细胞移植患者中，巨细胞病毒（CMV）感染仍然是一个严重的问题。移植后，CMV感染会导致肝炎，肝炎，肠炎和骨髓衰竭。 CMV血清阳性移植受者可以在感染发作时或在干细胞植入时用抗病毒剂（例如Ganciclovir）治疗，但Ganciclovir Therapy疗法与肾脏毒性和中性粒细胞计数的抑制有关。初步研究发现，使用CMV反应性细胞毒性T淋巴细胞（CTL）是一种有效且毒性较小的替代方法，可预防移植食谱中CMV感染。这项研究的目的是制定新的治疗策略来产生CMV反应性CTL，这些CTL可用于过养免疫疗法，并更好地了解细胞免疫反应对CMV。当前的研究集中在识别可用于刺激CMV反应性CTL的免疫主导肽。 CMV含有200多种蛋白质，但是两种蛋白质CMV蛋白PP65和IE1已被发现是免疫主导性的。我们发现肽CMV PP65 91-100被发现限于HLA-A*33的免疫优势肽，PP65 328-337是限于HLA-A*2402的免疫优势肽。现在，我们正在使用PP65的库和IE1的长度重叠肽，以识别新的I类和II类表位。在PP65和IE1肽中都发现了I类和II类表位。为了进一步表征I类纤维，测试了组成反应性15个氨基酸肽的9种氨基酸肽对CD8细胞的反应性。已经确定了几种PP65和IE1反应性肽9氨基酸。未来的研究将表征I类和II类表位的HLA限制。