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).
Our research is focused on novel immune-therapies to control the autoimmune response in T1D and in patients undergoing to islet transplantation.
- 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 is funded by the JDRF (5-CDA-2015-85-A-N)
- Targeting GLUT1 to inhibit autoreactive T cells. Upon activation, T cells up-regulate the glucose transporter GLUT1 to fulfill the bio-energetic needs for proliferation. Blocking GLUT1 with small molecules induces T cell exhaustion and unresponsiveness. The clinical translation of this approach would be to design an induction therapy with GLUT1 inhibitors in clinical islet transplantation to prevent autoimmunity recurrence. This project is funded by the JDRF (5-CDA-2015-85-A-N) (2-SRA-2019-756-S-B)
- Generation of high-performance regulatory T cells (Treg). Treg are a promising immune-modulatory tool to control autoimmunity, but their efficacy is limited by a short term persistence in vivo. We are generating high-performance Treg with improved survival and lifespan. Starting from naïve Treg precursors, we generate Treg with a stem cell memory phenotype in vitro for adoptively transfer in patients with T1D. This project is funded by the EFSD/JDRF/Lilly European Programme in T1D Research.
Di Dedda C, Vignali D, Piemonti L, Monti P. Pharmacological Targeting of GLUT1 to Control Autoreactive T Cell Responses. Int J Mol Sci. 2019 Oct 8;20(19)
Ma P, Nano R, Monti P, Melzi R, Sordi V, Mercalli A, Pellegrini S, Ponzoni M, Peccatori J, Messina C, Nocco A, Cardillo M, Scavini M, Magistretti P, Doglioni C, Ciceri F, Bloem SJ, Roep BO, Secchi A, Piemonti L. Islet Allotransplantation in the Bone Marrow of Patients With Type 1 Diabetes: A Pilot Randomized Trial. Transplantation. 2019 Apr;103(4):839-851
Vignali D, Cantarelli E, Bordignon C, Canu A, Citro A, Annoni A, Piemonti L, Monti P. Detection and Characterization of CD8+ Autoreactive Memory Stem T Cells in Patients With Type 1 Diabetes. Diabetes. 2018 May;67(5):936-945
Bordignon C, Canu A, Dyczko A, Leone S, Monti P. T-cell Metabolism as a Target to Control Autoreactive T Cells in β-Cell Autoimmunity. Curr Diab Rep. 2017 May;17(5):24
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 identi es 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 in uenced 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, Ma P, Piemonti L, Secchi A, Bonifacio E, Roncarolo MG, Battaglia M. Rapamycin monotherapy in patients with type 1 diabetes modi es CD4+CD25+FOXP3+ regulatory T cells. Diabetes 2008;57(9):2341-2347.
Monti P, Scirpoli M, Ma 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.