title: Inotuzumab ozogamicin murine analog-mediated B-cell depletion reduces anti-islet allo- and autoimmune responses.
abstract: B cells participate in the priming of the allo- and autoimmune responses, and their depletion can thus be advantageous for islet transplantation. Herein, we provide an extensive study of the effect of B-cell depletion in murine models of islet transplantation. Islet transplantation was performed in hyperglycemic B-cell-deficient(μMT) 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). Inotuzumab ozogamicin murine analog (anti-CD22 monoclonal antibody conjugated with calicheamicin [anti-CD22/cal]) efficiently depleted B cells in all three models of islet transplantation examined. Islet graft survival was significantly prolonged in B-cell-depleted mice compared with control groups in transplants of islets from BALB/c into C57BL/6 (mean survival time [MST]: 16.5 vs. 12.0 days; P = 0.004), from NOD.SCID into NOD (MST: 23.5 vs. 14.0 days; P = 0.03), and from BALB/c into NOD (MST: 12.0 vs. 5.5 days; P = 0.003). In the BALB/c into B-cell-deficient mice model, islet survival was prolonged as well (MST: μMT = 32.5 vs. WT = 14 days; P = 0.002). Pathology revealed reduced CD3(+) cell islet infiltration and confirmed the absence of B cells in treated mice. Mechanistically, effector T cells were reduced in number, concomitant with a peripheral Th2 profile skewing and ex vivo recipient hyporesponsiveness toward donor-derived antigen as well as islet autoantigens. Finally, an anti-CD22/cal and CTLA4-Ig-based combination therapy displayed remarkable prolongation of graft survival in the stringent model of islet transplantation (BALB/c into NOD). Anti-CD22/cal-mediated B-cell depletion promotes the reduction of the anti-islet immune response in various models of islet transplantation.
authors.affiliation: Transplant Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Michele
authors.initials: M
authors.lastname: Carvello
authors.forename: Alessandra
authors.initials: A
authors.lastname: Petrelli
authors.forename: Andrea
authors.initials: A
authors.lastname: Vergani
authors.forename: Kang Mi
authors.initials: KM
authors.lastname: Lee
authors.forename: Sara
authors.initials: S
authors.lastname: Tezza
authors.forename: Melissa
authors.initials: M
authors.lastname: Chin
authors.forename: Elena
authors.initials: E
authors.lastname: Orsenigo
authors.forename: Carlo
authors.initials: C
authors.lastname: Staudacher
authors.forename: Antonio
authors.initials: A
authors.lastname: Secchi
authors.forename: Kyri
authors.initials: K
authors.lastname: Dunussi-Joannopoulos
authors.forename: Mohamed H
authors.initials: MH
authors.lastname: Sayegh
authors.forename: James F
authors.initials: JF
authors.lastname: Markmann
authors.forename: Paolo
authors.initials: P
authors.lastname: Fiorina
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000737:chemistry / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects / Q000502:physiology; D015551:Autoimmunity / Q000187:drug effects*; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D016923:Cell Death / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D005260:Female; D006085:Graft Survival / Q000276:immunology; D000080045:Inotuzumab Ozogamicin; D007515:Islets of Langerhans / Q000187:drug effects* / Q000276:immunology*; D016381:Islets of Langerhans Transplantation / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D023001:Transplantation Tolerance / Q000187:drug effects / Q000276:immunology
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000080045:Inotuzumab Ozogamicin
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