Manuela Battaglia
Manuela Battaglia
affiliation: San Raffaele Scientific Institute
research area(s): Experimental Medicine, Immunity And Infection
Course: Basic and Applied Immunology
University/Istitution: Università Vita-Salute San Raffaele
1995 - Degree in Molecular Biology, University of Milan (Italy).
2001 - PhD Immunology Blood Center Southeastern Wisconsin, Milwaukee (USA)
1993 -1995 Undergraduate Student, Stem Cell Laboratory of Centro Trasfusionale e di Immunologia dei Trapianti, Ospedale Maggiore, Milano (Italy).
1995-1998 Predoctoral Fellow, Experimental Oncology Hematology and Immunology Laboratory, Maugeri Foundation, Pavia Medical center, Pavia (Italy).
1998-2001 Pre/Postdoctoral Fellow, Molecular Genetics laboratory, Blood Center Southeastern Wisconsin, Milwaukee, WI (USA).
2001-2004 Senior Postdoctoral Fellow, San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Milano (Italy).
2004-2008 Project Leader, HSR-TIGET, Milano (Italy).
2008-today Research Associate, San Raffaele Diabetes Research Institute (HSR-DRI), Milano (Italy)
Tolerance in Type 1 Diabetes and Pancreatic Islet Transplantation

AIM: Type 1 diabetes (T1D) is the result of a T-lymphocyte dependent autoimmune process that specifically destroys the insulin-secreting beta-cells of the pancreas. To down-modulate T cell responses and re-establish immunological self-tolerance to the beta-islets is fundamental for the definitive cure of T1D. Immunological tolerance can be achieved by the induction of Ag-specific T regulatory cells (Tregs) that suppress effector T cells specific for pancreatic beta-islets, while leaving the rest of the immune system intact. The main goals of the laboratory are to characterize the autoimmune responses occurring in T1D patients and to define new approaches for re-establishing self-tolerance.

PRECLINICAL MODEL(S) /DISEASE FOCUS: Disease: Autoimmune, insulin-dependent diabetes, islet transplantation. Mouse-preclinical models: Non-obese diabetes (NOD) spontaneous autoimmune diabetes. Islet alllo-transplantation model (C57Bl/6, BALB/C). TCR transgenic model (BDC2.5). Viral infection (acute LCMV) model (near future). Xenogeneic graft-versus-host disease (xGvHD) model in NOG and NSG. We also use blood/pancreatic lymph nodes from new-onset or long-lasting patients with T1D.
Battaglia M, Stabilini A, Roncarolo MG. Rapamycin selectively expands CD4+CD25+ FOXP3+ regulatory T cells. Blood 2005, 105:4743-4748

Battaglia M, Stabilini A, Migliavacca B, Horejs-Hoeck J, Kaupper T, Roncarolo MG.
Rapamycin promotes expansion of functional CD4+CD25+FOXP3+ regulatory T cells of both healthy subjects and type 1 diabetic patients. The Journal of Immunology 2006, 177:8338-8347

Battaglia M, Gregori S, Bacchetta R, Roncarolo MG. Tr1 cells: from the discovery to their clinical application. Seminars in Immunology 2006, 18: 120-7

Roncarolo MG, Battaglia M. T regulatory cell immunotherapy for tolerance to self- and allo-antigens in humans. Nature Reviews Immunology 2007, 7:585-598

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, 57:1-7

Valle A, Jofra T, Stabilini A, Atkinson M, Roncarolo MG, Battaglia M. Rapamycin prevents and breaks the anti-CD3i nduced tolerance in NOD mice. Diabetes 2009, 58: 875-881

Gagliani N, Jofra T, Stabilini A, Valle A, Atkinson M, Roncarolo MG, Battaglia M.
Antigen-specific dependence of Tr1-cell therapy in preclinical models of islet transplantation. Diabetes 2010; 59: 433-439

Battaglia M. Potential T regulatory cell therapy in transplantation: how far have we come and how far can we go? Transplantation 2010; 23(8):761-70

Huber S, Gagliani N, Esplugues E, O Connor W Jr, Huber FJ, Chaudhry A, Kamanaka M, Kobayashi Y, Booth CJ, Rudensky AY, Roncarolo MG, Battaglia M, Flavell RA. Th17 cells express IL-10Ra and are controlled by Foxp3- and Foxp3+ regulatory CD4+ T cells in an IL-10 dependent manner. Immunity 2011; 34(4):554-65

Tresoldi E, Dell Albani I, Stabilini A, Jofra T, Valle A, Gagliani N, Bondanza A, Roncarolo MG, Battaglia M. Stability of human rapamycin-expanded CD4+CD25+ T regulatory cells. Haematologica 2011; in press
Project Title:
Immunological characterization of pancreas-draining lymph-nodes of type 1 diabetes patients.
Type 1 diabetes (T1D) is the result of a T-lymphocyte dependent autoimmune process that specifically destroys the insulin-secreting beta-cells of the pancreas. Blockade of autoaggressive T cells and re-establishment of tolerance to the beta-islets is fundamental for the definitive cure of autoimmune diabetes. Immunological tolerance can be achieved by the induction of a subset of T cells, named T regulatory cells (Tregs), that specifically suppress the effector T cells reacting against pancreatic beta-islets, while leaving the rest of the immune system intact. An altered balance between pathogenic and regulatory pathways in autoimmunity has been hypothesized and at times demonstrated in peripheral blood of T1D patients. However, for obvious reasons, our knowledge at the site targeted by the autoimmune attack (i.e. the pancreas) in humans is scanty.
We have the unique opportunity to collect pancreatic lymph nodes from T1D patients and from non-diabetic controls. This cell source will be used to extensively characterize the immune responses of T1D individuals in their target organ.
This study will:
1) provide crucial information regarding the immunological status of the target organ in T1D subjects, 2) lead to the identification of new disease-specific markers, and 3) lead to the characterization of Tregs which reside in the pancreas as compared to those which circulate in the peripheral blood.

Project Title:
Dissecting the mechanisms that lead to type 1 autoimmune diabetes in humans: genetics meets immunology.
Type 1 diabetes (T1D) is a common autoimmune disease caused by predisposing genetic factors in the presence of a permissive environment. It is now evident that loss of immunological tolerance to beta-cells leads to T1D. PTPN22 encodes for PEP(mouse)/LYP(human), a lymphoid tyrosin phosphatase that down-regulates T cell activation. A single nucleotide polymorphism leads to an Arg (R) to Trp (W) substitution in the PTPN22 gene and T1D risk is increased 2 fold in individuals carrying the variant form. The mechanism by which PTPN22 acts as an autoimmune susceptibility locus for T1D remains unclear. Given the central role of PTPN22 in the development of T1D and other autoimmune diseases this project aims at:
1) Dissecting the role of PTPN22 in T regulatory (Treg) and effector (Teff) cells in T1D patients vs. healthy individuals. Specifically, we will address whether PTPN22 R620W homozygous T1D carriers bear altered memory, Treg, Teff cell frequency and how does this correlate with the clinical profile of the disease; how is LYP expression involved in Teff versus Treg differentiation, stability and response after TCR activation; and whether efficient knockdown of PTPN22 in Treg and Teff cells alter their suppressive activity or effector profile.
2) Dissecting the role of PTPN22 in Treg/Teff in various mouse models of T1D. Specifically, we will address the effect on spontaneous autoimmune diabetes in NOD mice in the absence of PTPN22 signaling; how PTPN22 affects the processes of thymic selection, Treg/Teff cell homeostasis and function in BDC2.5 TCR transgenic mice; and what is the effect of PTPN22 absence in a mouse model of virally-induced T1D and in the generation of protective antiviral immunity.
All in all, understanding the mechanisms by which dominant gene variants alter biology is fundamental for dissecting the still unknown mechanisms that lead to autoimmunity and may help in defining new therapeutics and T1D subgroups.