title: TIM4 Regulates the Anti-Islet Th2 Alloimmune Response.
abstract: The role of the novel costimulatory molecule TIM4 in anti-islet response is unknown. We explored TIM4 expression and targeting in Th1 (BALB/c islets into C57BL/6 mice) and Th2 (BALB/c islets into Tbet(-/-) C57BL/6 mice) models of anti-islet alloimmune response and in a model of anti-islet autoimmune response (diabetes onset in NOD mice). The targeting of TIM4, using the monoclonal antibody RMT4-53, promotes islet graft survival in a Th1 model, with 30% of the graft surviving in the long term; islet graft protection appears to be mediated by a Th1 to Th2 skewing of the immune response. Differently, in the Th2 model, TIM4 targeting precipitates graft rejection by further enhancing the Th2 response. The effect of anti-TIM4 treatment in preventing autoimmune diabetes was marginal with only minor Th1 to Th2 skewing. B-Cell depletion abolished the effect of TIM4 targeting. TIM4 is expressed on human B-cells and is upregulated in diabetic and islet-transplanted patients. Our data suggest a model in which TIM4 targeting promotes Th2 response over Th1 via B-cells. The targeting of TIM4 could become a component of an immunoregulatory protocol in clinical islet transplantation, aiming at redirecting the immune system toward a Th2 response.
authors.affiliation: Transplantation Research Center, Division of Nephrology, Boston Children's Hospital and Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02215, USA.|Transplant Medicine, Ospedale San Raffaele, Milan, 20132, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Vergani
authors.affiliation: Transplantation Research Center, Division of Nephrology, Boston Children's Hospital and Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02215, USA.|University of Salento, Lecce, 73100, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Gatti
authors.affiliation: Transplant Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
authors.forename: Kang M
authors.initials: KM
authors.lastname: Lee
authors.affiliation: Transplantation Research Center, Division of Nephrology, Boston Children's Hospital and Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02215, USA.|Transplant Medicine, Ospedale San Raffaele, Milan, 20132, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: D'Addio
authors.affiliation: Transplantation Research Center, Division of Nephrology, Boston Children's Hospital and Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02215, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Tezza
authors.affiliation: Transplantation Research Center, Division of Nephrology, Boston Children's Hospital and Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02215, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Chin
authors.affiliation: Transplantation Research Center, Division of Nephrology, Boston Children's Hospital and Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02215, USA.
authors.forename: Roberto
authors.initials: R
authors.lastname: Bassi
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02215, USA.
authors.forename: Ze
authors.initials: Z
authors.lastname: Tian
authors.affiliation: Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND, 58104, USA.
authors.forename: Erxi
authors.initials: E
authors.lastname: Wu
authors.affiliation: Transplant Medicine, Ospedale San Raffaele, Milan, 20132, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Maffi
authors.affiliation: Transplantation Research Center, Division of Nephrology, Boston Children's Hospital and Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02215, USA.
authors.forename: Moufida
authors.initials: M
authors.lastname: Ben Nasr
authors.affiliation: Transplant Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
authors.forename: James I
authors.initials: JI
authors.lastname: Kim
authors.affiliation: Transplant Medicine, Ospedale San Raffaele, Milan, 20132, Italy.|Vita-Salute San Raffaele University, Milan, 20132, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Secchi
authors.affiliation: Transplant Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
authors.forename: James F
authors.initials: JF
authors.lastname: Markmann
authors.affiliation: Department of Immunology, University of Pittsburgh, Pittsburgh, PA, 15213, US.
authors.forename: David M
authors.initials: DM
authors.lastname: Rothstein
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.
authors.forename: Laurence A
authors.initials: LA
authors.lastname: Turka
authors.affiliation: Transplantation Research Center, Division of Nephrology, Boston Children's Hospital and Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02215, USA.
authors.forename: Mohamed H
authors.initials: MH
authors.lastname: Sayegh
authors.affiliation: Transplantation Research Center, Division of Nephrology, Boston Children's Hospital and Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02215, USA.|Transplant Medicine, Ospedale San Raffaele, Milan, 20132, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Fiorina
mesh_terms: D000328:Adult; D000818:Animals; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation; D016207:Cytokines / Q000032:analysis / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000401:mortality / Q000601:surgery; D003922:Diabetes Mellitus, Type 1 / Q000601:surgery; D005260:Female; D006085:Graft Survival / Q000276:immunology; D006801:Humans; D007515:Islets of Langerhans / Q000473:pathology; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008875:Middle Aged; D015996:Survival Rate; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D059467:Transcriptome; D014184:Transplantation, Homologous
chemical_list: D016207:Cytokines; D008565:Membrane Proteins; C500399:TIM-4 protein, mouse