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TRANSPLANT IMMUNOLOGY OF IL2 IFNY DOUBLE KNOCKOUT MICE

IL2 IFNY 双敲除小鼠的移植免疫学

基本信息

批准号：
6532607
负责人：
Martin S Zand
金额：
$ 12.04万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-09-01 至 2003-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6532607
关键词：
T lymphocyte blocking antibody cellular immunity gene targeting genetically modified animals humoral immunity immune tolerance /unresponsiveness interferon gamma interleukin 12 interleukin 15 interleukin 2 interleukin 4 laboratory mouse pancreas transplantation secretion transplant rejection transplantation immunology

项目摘要

Approximately, 10,000 renal and 1,500 pancreas transplants (allografts) are performed annually in the United States. Despite aggressive immune suppression, hundreds of these organs are lost each year to immune mediated rejection. Because the number of individuals waiting for a transplant greatly exceeds the supply of donated organs, transplant rejection directly contributes to the shortage of these organs. Intragraft expression of the cytokines interleukin 2 and interferon gamma (IFN-gamma) has been found to be markers for clinical and experimental allograft rejection. Although most clinical protocols for immune suppression in transplant patients can reduce the levels of IL-2 and IFN-gamma, immune mediated rejection still occurs. Currently, no experimental models exist in which allograft rejection can be studied when both IL-2 and IFN-gamma are completely absent. The goal of this proposal is to create a transgenic mouse model with targeted gene disruption of both the IL-2 and IFN-gamma genes, and to study the immune responses to transplanted issue in these mice. We have successfully bred IL-2 IFN-gamma double knockout mice (DKO). The mice are generally healthy, have normal litters, and survive as long as 6 months in sterile housing. Our preliminary data indicate that the DKO mice develop a much milder form of the autoimmune colitis seen in the IL-2 single knockout mice. DKO mice can mount a strong delayed-type hypersensitivity. response to a foreign protein antigen. Finally, the DKO mice have a profound defect in B cell maturation. Our specific goals in this proposal are to (1) characterize the ability of the DKO mice to mount cellular and humoral immune responses and (2) determine the outcome of the immune response to pancreatic allografts in the absence of IL-2 and IFN-gamma (i.e. rejection or tolerance). First, we will study the ability of DKO mice to generate delayed -type hypersensitivity responses to histocompatibility antigens (MHC), generate antibodies after immunization, and generate cytotoxic T-lymphocyte. Second, we will render DKO mice diabetic using streptozotocin, and then perform pancreatic islet cell transplantation from MHC disparate donors. Allograft survival will be monitored we hypothesize that the DKO mice will reject islet allografts, and that the mechanisms of rejection will involved IL-4 or other T cell growth factors and cytotoxic T cells. The cytokine milieu and cell phenotypes involved will be identified by quantitative polymerase chain reaction and fluorescence activated cell sorting. In contrast, if the DKO mice are tolerant to islet allografts, we will determine the mechanism by adoptive transfer of tolerance inducing T lymphocyte subsets.

大约10000例肾脏移植和1500例胰腺移植（同种异体移植）