Inotuzumab Ozogamicin Murine Analog–Mediated B-Cell Depletion Reduces Anti-islet Allo- and Autoimmune Responses.

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
(mMT) 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: mMT = 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 donorderived
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. Diabetes 61:155–165, 2012