Transplanted organs, tissues and cells are targets of the host immune response, that, in the absence of adequate immunesuppression, lead to graft loss. Host immune response is characterized by the activation and clonal expansion of allo-reactive T cells and, in the case of transplant in subjects with autoimmunity, also of memory auto-reactive clones. Current immunosuppressive regimens used in clinical transplantiation showed limited efficacy and important side effects. The aim of Transplant immunology Unit is to determine mechanisms of proliferation and activation of T cells in clinical transplant to identify novel molecular targets for a selective and effective control of T cell responses in transplantation. In particular, this group aims to determine:
- the role of memory stem T cells in long term memory maintenance;
- the role of IL-7 mediated homeostatic proliferation of T cells during immunosuppression therapy;
- the possibility to control the T cell response with modulators of bio-energetic metabolism (glycolysis, oxidative phosphorylation and glutaminolysis).
This group has identified IL-7 as a fundamental mediator of T cell expansion post islet transplantation in patients with type 1 diabetes. IL-7 is elevated in patients who develop lymphopenia following immunosuppressive therapy. IL-7 driven T cell proliferation is refractory to most of immunosuppressive compounds. Moreover IL-7 reduces the suppressive activity of regulatory T cells.
- Memory stem T cells (Tscm). The main hypothesis is that patients with type 1 diabetes develop Tscm specific for islet antigens, that these cells survive as quiescent cells for years and that they get re-activated by islet transplantation and affect the graft. The aim is to determine the pathogenic role of Tscm in islet transplantation and to identify novel molecular targets for selective inhibition of Tscm. This project was funded until 2020 from the Juvenile Diabetes Research Foundation (JDRF).
- Immuno-metabolism of autoreactive T cells. The hypothesis is that activated T cells have an extra-ordinary bio-energetic need, which if not fulfilled lead to apoptosis and unresponsiveness. The aim is to inhibit T cell metabolism using novel classes of metabolic inhibitors for a limited time and after antigen-specific activation to induce a permanent deletion of autoreactive clones. The clinical translation of this approach would be to design an induction therapy with metabolic inhibitors in clinical islet transplantation which represent an antigen specific T cell activation.
Vignali D, Gürth CM, Pellegrini S, Sordi V, Sizzano F, Piemonti L, Monti P. IL-7 mediated homeostatic expansion of human CD4+CD25+FOXP3+ regulatory T cells after depletion with anti-CD25 monoclonal antibody. Transplantation 2016 Sep;100(9):1853-61.
Vignali D, Monti P. Targeting Homeostatic T Cell Proliferation to Control Beta-Cell Autoimmunity. Curr Diab Rep. 2016. 16(5). 40.
Monti P, Piemonti L. Homeostatic T cell proliferation after islet transplantation. Clin Dev Immunol. 2013;2013:217934.
Monti P, Brigatti C, Krasmann M, Ziegler AG, Bonifacio E. Concentration and activity of the soluble form of the Interleukin-7 Receptor alpha in type I diabetes identifies an interplay between hyperglycemia and immune function. Diabetes 2013 Jul; 62(7): 2500–2508.
Heninger AK, Monti P, Wilhelm C, Schwaiger P, Kuehn D, Ziegler AG, Bonifacio E. Activation of islet autoreactive naive T cells in infants is influenced by homeostatic mechanisms and antigen presenting capacity. Diabetes. 2013. 62: 2059-2066.
Heninger AK, Theil A, Wilhelm C, Petzold C, Huebel N, Kretschmer K, Bonifacio E, Monti P. Interleukin-7 abrogates suppressive activity of human CD4+CD25+FOXP3+ T regulatory cells and allows expansion of alloreactive and autoreactive T cells. J Immunol. 2012;189 (12): 5649-5658.
Monti P, Brigatti C, Heninger AK, Scirpoli M, Bonifacio E. Disengaging the IL-2 receptor with Daclizumab enhances IL-7–mediated proliferation of CD4+ and CD8+ T cells. Am J Transplant. 2009. 9: 2727–2735.
Monti P, Heninger AK, Bonifacio E. Differentiation, expansion and homeostasis of autoreactive T cells in type I diabetes mellitus. Curr Diab Rep. 2009 Apr;9(2):113-8.
Monti P, Scirpoli M, Maffi P, Piemonti L, Secchi A, Bonifacio E, Roncarolo MG, Battaglia M. Rapamycin monotherapy in patients with type 1 diabetes modifies CD4+CD25+FOXP3+ regulatory T cells. Diabetes 2008;57(9):2341-2347.
Monti P, Scirpoli M, Maffi P, Ghidoli N, De Taddeo F, Bertuzzi F, Piemonti L, Falcone M, Secchi A, Bonifacio E. Islet transplantation in autoimmune diabetes patients induces homeostatic cytokines that expand autoreactive memory T cells. J Clin Invest. 2008 May; 118(5):1806–1814.