Paolo Fiorina
Paolo Fiorina
affiliation: Harvard Medical School, Boston MA, USA
research area(s): Experimental Medicine, Immunity And Infection
Course: Basic and Applied Immunology
University/Istitution: Università Vita-Salute San Raffaele
10/1982-07/1987 B.S., Istituto Scientifico Sant" Alessandro, Bergamo, Italy
10/1987-10/1993 M.D., Cum laude, Universita" degli Studi di Milano, Milan, Italy
10/1998-11/2002 Ph.D., Universita" degli Studi di Milano, Milan, Italy

Postdoctoral Training:
11/1993-11/1997 Residency in Allergy and Clinical Immunology, Universita" degli Studi di Parma, Parma, Italy
10/2004-07/2006 Research Fellowship, Harvard Medical School, Boston, MA
10/2002-06/2008 Residency in Internal Medicine, Vita-Salute San Raffaele University, Milan, Italy

Faculty Academic Appointments
07/2006-09/2009 Instructor, Harvard Medical School, Boston, MA
09/2009- Assistant Professor, Harvard Medical School, Boston, MA

Appointments at Hospitals/Affiliated Institutions

10/1993-10/1997 Resident in Clinical Immunology, Department of Medicine, Ospedale Maggiore di Parma, Parma, Italy

10/1997-07/1999 Fellow in Transplantation Medicine, Department of Medicine, San Raffaele Scientific Institute, Milan, Italy

07/1999-10/2004 Staff Physician, Department of Medicine, San Raffaele Scientific Institute, Milan, Italy

10/2004-01/2007 Research Fellow, Department of Medicine/Nephrology Division, Children's Hospital Boston

01/2007- Associate Scientist, Department of Medicine/Nephrology Division, Children's Hospital Boston
Beginning in my early years of medical school, I have been fascinated by islet cell transplantation - that is, if normal functioning pancreatic islet cells could be successfully transplanted into diabetic patients, the well-known ravages of diabetes could be prevented. I had the opportunity to work on islet-transplanted patients in Italy at the San Raffaele Scientific Institute, where one of the largest cohort studies was being performed.

I obtained my medical degree in Milan in 1992, and subsequently completed my postgraduate training in Allergy and Clinical Immunology in Parma. Later, I moved to Milan for the PhD in Internal Medicine at the University of Milan. I have since then been a full time faculty member at the San Raffaele Scientific Institute of Milan. In this position, I worked in the transplantation team under the mentorship of Professor Guido Pozza (past president of the Italian Diabetes Association), and Professor Antonio Secchi (IPITA president). During these 6 years I have spent most of my life working with patients affected by type 1 diabetes and undergoing islet transplantation.

In 2004 (October) I joined the Transplantation Research Center at the Children"s Hospital/Brigham and Women"s Hospital/Harvard Medical School, directed by Dr. Mohamed Sayegh to address the basis of immunobiology. My research fellowship at the Brigham allowed me to expand my research interest and to improve my expertise in the field of transplant immunology.
After becoming a faculty member at Harvard Medical School in 2006 (July), I became interested in studying new approaches to abrogate autoimmunity in diabetic patients. I realized that so far most of the immunosuppressive protocols have been unsuccessful in suppressing autoimmunity, often because they are not specifically customized to counteract autoimmunity. My idea was to realize the ultimate immunosuppressive protocol by combining depleting agents with drugs capable of counteracting the following homeostatic proliferation.
I am actually further strengthening my research skills and knowledge in the field of transplant immunology. Ultimately, I envisage using the skills and expertise I have gained during the last months in Boston, to find the solution for allograft rejection and autoimmune diabetes.
I am fortunate to be able to work in the Transplantation Research Center, which has longstanding experience with a variety of animal models of transplantation as well as protocols to achieve longterm allograft acceptance. All the necessary tools and equipment necessary to complete my projects are readily available in our center. I am excited by the potential wealth of knowledge that my studies can unleash in the areas of islet allograft rejection, and I believe I can complete my mission, which is again to prevent allograft rejection and autoimmune diabetes.
Selected Peer-reviewed Publications (over 84)

1. Fiorina P et al. Effects of kidney-pancreas transplantation on atherosclerotic risk factors and endothelial function in patients with uremia and type 1 diabetes. Diabetes. 2001;50(3):496-501
2. Fiorina P et al. Islet transplantation is associated with improvement of renal function among uremic patients with type I diabetes mellitus and kidney transplants. J Am Soc Nephrol. 2003;14(8):2150-8
3. Fiorina P et al. Long-term beneficial effect of islet transplantation on diabetic macro-/microangiopathy in type 1 diabetic kidney-transplanted patients. Diabetes Care. 2003;26(4):1129-36
4. Fiorina P et al. Normalization of multiple hemostatic abnormalities in uremic type 1 diabetic patients after kidney-pancreas transplantation. Diabetes. 2004;53(9):2291-300
5. Fiorina P et al. Islet transplantation is associated with an improvement of cardiovascular function in type 1 diabetic kidney transplant patients. Diabetes Care. 2005;28(6):1358-65
6. Fiorina P et al. Natural history of kidney graft survival, hypertrophy, and vascular function in end-stage renal disease type 1 diabetic kidney-transplanted patients: beneficial impact of pancreas and successful islet cotransplantation. Diabetes Care. 2005;28(6):1303-10
7. Fiorina P et al. Characterization of donor dendritic cells and enhancement of dendritic cell efflux with CC-chemokine ligand 21: a novel strategy to prolong islet allograft survival. Diabetes. 2007;56(4):912-20
8. Fiorina P et al. Metabolic and immunological features of the failing islet transplanted patient. Diabetes Care. 2008 Mar;31(3):436-8. Epub 2007 Dec 10
9. Fiorina P et al. Targeting CD22 reprograms B cells and reverses autoimmune diabetes. Diabetes. 2008; Nov;57(11):3013-24. Epub 2008 Aug 8
10. Fiorina P et al. The clinical impact of islet transplantation. Am J Transplant. 2008;8(10):1990-7
11. Fiorina P et al. Immunomodulatory function of bone marrow-derived mesenchymal stem cells in experimental autoimmune type 1 diabetes. J Immunol. 2009 Jul 15;183(2):993-1004. Epub 2009 Jun 26
12. Folli F et al., Fiorina P. Proteomics reveals novel oxidative and glycolytic mechanisms in type 1 diabetic patients" skin which are normalized by kidney-pancreas transplantation. PLoS One. 2010 Mar 29;5(3):e9923.
13. Vergani A et al., Fiorina P. A novel clinically relevant strategy to abrogate autommunity and regulate alloimmunity in NOD mice. Diabetes. 2010 Sep;59(9):2253-64
14. Petrelli A et al., Fiorina P. Improved function of circulating angiogenic cells is evident in type 1 diabetic islet-transplanted patients. Am J Transplant. 2010 Dec;10(12):2690-700
15. Fiorina P et al. Targeting the CXCR4-CXCL12 axis mobilizes autologous hematopoietic stem cells and prolongs islet allograft survival via PD-L1. J Immunol. 2011 Jan 1;186(1):121-31. Epub 2010 Dec 3
Project Title:
1. IL-21 induces Treg dysfunction during the late-phase of alloimmune response
Interleukin-21 (IL-21) has been shown to orchestrate the immune response, yet its role in the alloimmune response and in Treg survival and function is unclear. The interplay between IL-21/IL-21R signaling, FoxP3 expression and Treg survival and function will be evaluated in vitro and in vivo. Our preliminary data suggested that IL-21R expression decreases on T- and B-cells in vitro and increases in the graft in vivo, while IL-21 levels increase in vitro and in vivo during anti-CD3/-CD28 stimulation/allostimulation in the late-phase of the alloimmune response. In vitro, IL-21/IL-21R signaling enhances the T-cell response during anti-CD3/-CD28 stimulation/allostimulation, prevents Treg generation, inhibits Treg function, induces Treg apoptosis and reduces FoxP3 and FoxP3-dependent-gene transcripts, without affecting FoxP3 methylation status. We hypothesize that L-21 interferes with different checkpoints of the FoxP3-Treg chain.

Project Title:
2. B-cell depletion and deficiency reduces anti-islet immune response
B-cells participate in the priming of the allo- and autoimmune responses, and their depletion can thus be advantageous for islet transplantation. Herein, we will provide an extensive study of the effect of B-cells depletion in murine models of islet transplantation. Our preliminary data performed in hyperglycemic B-cell-deficient (┬ÁMT) mice, in a purely alloimmune setting (BALB/c into hyperglycemic C57BL/6), in a purely autoimmune setting (NOD.SCID into hyperglycemic NOD) and in a mixed allo-/autoimmune setting (BALB/c into hyperglycemic NOD) delineate the effect of B-cell depletion on the anti-islet immune response and on graft survival. Mechanistically, the absence/depletion of effector T-cells were reduced in number, concomitant with a peripheral Th2 profile skewing and ex vivo recipient hyporesponsiveness toward donor-derived antigen (BALB/c) as well as islet autoantigens (BDC2.5 and IGRP).