Our recent data show that cynomolgus transplant recipients are resistant to the induction of chimerism and transplant tolerance until the pro-inflammatory state that arises in the peri-transplant period and continues for weeks to months thereafter abates. Projects 1 and 2 place heavy emphasis upon the role of inflammation in influencing the allograft response toward or away from transplant tolerance. In accordance with this logic, Core B will interact with all of the Project 1 and 2 in vivo models, by monitoring and characterizing the state of inflammation and immunity via QRT-PCR in the cynomolgus allograft recipients. Using a panel of custom made reagents crafted for use in cynomolgus monkeys and a powerful pre-amplification technique, we can assess transcription of over 65 genes in a small tissue sample. Going forward we will further develop a single cell PCR method to provide detailed information about the frequency of T cell subsets in recipient blood or tissues. The goal is to favorably tilt the balance of immunity toward allograft protection and tolerance by controlling adverse inflammation. T alpha1 antitrypsin (AAT), an acute phase reactant and serine protease blocker is a potential agent for achieving such balance. It has been given safely as replacement therapy to patients with the AAT gene defect. This protein possesses interesting anti-inflammatory and anti-thrombotic effects. It is a potent islet cytoprotectant and although lacking direct effects upon T cells promotes T cell tolerance. This and other novel agents will be characterized in Core B for use in the Project 1 and 2 models.
In short, we will sequentially monitor the NHP allograft recipients to characterize a state of inflammation in which T cells do not commit to tolerant-resistant phenotypes. Expression of pro-inflammatory cytokines is clearly detrimental to commitment to the regulatory T cell phenotype and the viability of islet transplants.
|Oura, T; Hotta, K; Lei, J et al. (2016) Immunosuppression With CD40 Costimulatory Blockade Plus Rapamycin for Simultaneous Islet-Kidney Transplantation in Nonhuman Primates. Am J Transplant :|
|Oura, Tetsu; Ko, Dicken S C; Boskovic, Svjetlan et al. (2016) Kidney Versus Islet Allograft Survival After Induction of Mixed Chimerism With Combined Donor Bone Marrow Transplantation. Cell Transplant 25:1331-41|
|Hotta, Kiyohiko; Aoyama, Akihiro; Oura, Tetsu et al. (2016) Induced regulatory T cells in allograft tolerance via transient mixed chimerism. JCI Insight 1:|
|Kant, Cavit D; Akiyama, Yoshinobu; Tanaka, Katsunori et al. (2015) Both rejection and tolerance of allografts can occur in the absence of secondary lymphoid tissues. J Immunol 194:1364-71|
|Wang, Ping; Schuetz, Christian; Vallabhajosyula, Prashanth et al. (2015) Monitoring of Allogeneic Islet Grafts in Nonhuman Primates Using MRI. Transplantation 99:1574-81|
|Tonsho, M; Lee, S; Aoyama, A et al. (2015) Tolerance of Lung Allografts Achieved in Nonhuman Primates via Mixed Hematopoietic Chimerism. Am J Transplant 15:2231-9|
|Oura, Tetsu; Hotta, Kiyohiko; Cosimi, A B et al. (2015) Transient mixed chimerism for allograft tolerance. Chimerism 6:21-6|
|Yamada, Y; Nadazdin, O; Boskovic, S et al. (2015) Repeated Injections of IL-2 Break Renal Allograft Tolerance Induced via Mixed Hematopoietic Chimerism in Monkeys. Am J Transplant 15:3055-66|
|Granados, Jose M M; Benichou, Gilles; Kawai, Tatsuo (2015) Hematopoietic stem cell infusion/transplantation for induction of allograft tolerance. Curr Opin Organ Transplant 20:49-56|
|Scalea, Joseph R; Villani, Vincenzo; Gillon, Bradford C et al. (2014) Development of antidonor antibody directed toward non-major histocompatibility complex antigens in tolerant animals. Transplantation 98:514-9|
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