PMID- 26580221
OWN - NLM
STAT- MEDLINE
DCOM- 20160617
LR  - 20181113
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 10
IP  - 11
DP  - 2015
TI  - Immune Depletion in Combination with Allogeneic Islets Permanently Restores 
      Tolerance to Self-Antigens in Diabetic NOD Mice.
PG  - e0142318
LID - 10.1371/journal.pone.0142318 [doi]
LID - e0142318
AB  - The destruction of beta cells in type 1 diabetes (T1D) results in loss of insulin 
      production and glucose homeostasis. Treatment of non-obese diabetic (NOD) mice 
      with immune-depleting/modulating agents (e.g., anti-CD3, murine 
      anti-thymocyte-globulin (mATG)) can lead to diabetes reversal. However, for 
      preclinical studies with these and other agents seeking to reverse disease at 
      onset, the necessity for exogenous insulin administration is debated. 
      Spontaneously diabetic NOD mice were treated with a short-course of mATG and 
      insulin provided as drug therapy or by way of allogeneic islet implants. Herein 
      we demonstrate that exogenous insulin administration is required to achieve 
      disease reversal with mATG in NOD mice. Unexpectedly, we also observed that 
      provision of insulin by way of allogeneic islet implantation in combination with 
      mATG leads to a pronounced reversal of diabetes as well as restoration of 
      tolerance to self-islets. Expansion/induction of regulatory cells was observed in 
      NOD mice stably cured with mATG and allogeneic islets. These data suggest that 
      transient provision of allogeneic insulin-producing islets might provide a 
      temporary window for immune depletion to be more effective and instilling stable 
      tolerance to endogenous beta cells. These findings support the use of a never 
      before explored approach for preserving beta cell function in patients with 
      recent onset T1D.
FAU - Gagliani, Nicola
AU  - Gagliani N
AD  - Diabetes Research Institute (DRI), IRCCS San Raffaele Scientific Institute, 
      Milan, Italy.
AD  - Vita-Salute San Raffaele University, Milan, Italy.
FAU - Jofra, Tatiana
AU  - Jofra T
AD  - Diabetes Research Institute (DRI), IRCCS San Raffaele Scientific Institute, 
      Milan, Italy.
FAU - Posgai, Amanda L
AU  - Posgai AL
AD  - Department of Pathology, Immunology, and Laboratory Medicine, College of 
      Medicine, University of Florida, Gainesville, FL, 32610, United States of 
      America.
FAU - Atkinson, Mark A
AU  - Atkinson MA
AD  - Department of Pathology, Immunology, and Laboratory Medicine, College of 
      Medicine, University of Florida, Gainesville, FL, 32610, United States of 
      America.
FAU - Battaglia, Manuela
AU  - Battaglia M
AD  - Diabetes Research Institute (DRI), IRCCS San Raffaele Scientific Institute, 
      Milan, Italy.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20151118
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Antilymphocyte Serum)
RN  - 0 (Autoantigens)
RN  - 0 (Insulin)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Animals
MH  - Antibodies, Monoclonal/administration & dosage/immunology
MH  - Antilymphocyte Serum/*administration & dosage
MH  - Autoantigens/immunology
MH  - Diabetes Mellitus, Type 1/*drug therapy/immunology/physiopathology
MH  - Glucose/metabolism
MH  - Humans
MH  - Immune Tolerance
MH  - Insulin/*administration & dosage/metabolism
MH  - Insulin-Secreting Cells/drug effects/pathology/transplantation
MH  - Mice
MH  - Mice, Inbred NOD
MH  - *Transplantation, Homologous
PMC - PMC4651367
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2015/11/19 06:00
MHDA- 2016/06/18 06:00
PMCR- 2015/11/18
CRDT- 2015/11/19 06:00
PHST- 2015/05/21 00:00 [received]
PHST- 2015/10/19 00:00 [accepted]
PHST- 2015/11/19 06:00 [entrez]
PHST- 2015/11/19 06:00 [pubmed]
PHST- 2016/06/18 06:00 [medline]
PHST- 2015/11/18 00:00 [pmc-release]
AID - PONE-D-15-21988 [pii]
AID - 10.1371/journal.pone.0142318 [doi]
PST - epublish
SO  - PLoS One. 2015 Nov 18;10(11):e0142318. doi: 10.1371/journal.pone.0142318. 
      eCollection 2015.