Immune Depletion in Combination with Allogeneic Islets Permanently Restores Tolerance to Self-Antigens in Diabetic NOD Mice
Standard
Immune Depletion in Combination with Allogeneic Islets Permanently Restores Tolerance to Self-Antigens in Diabetic NOD Mice. / Gagliani, Nicola; Jofra, Tatiana; Posgai, Amanda L; Atkinson, Mark A; Battaglia, Manuela.
In: PLOS ONE, Vol. 10, No. 11, 2015, p. e0142318.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - Immune Depletion in Combination with Allogeneic Islets Permanently Restores Tolerance to Self-Antigens in Diabetic NOD Mice
AU - Gagliani, Nicola
AU - Jofra, Tatiana
AU - Posgai, Amanda L
AU - Atkinson, Mark A
AU - Battaglia, Manuela
PY - 2015
Y1 - 2015
N2 - 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.
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.
KW - Animals
KW - Antibodies, Monoclonal
KW - Antilymphocyte Serum
KW - Autoantigens
KW - Diabetes Mellitus, Type 1
KW - Glucose
KW - Humans
KW - Immune Tolerance
KW - Insulin
KW - Insulin-Secreting Cells
KW - Mice
KW - Mice, Inbred NOD
KW - Transplantation, Homologous
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1371/journal.pone.0142318
DO - 10.1371/journal.pone.0142318
M3 - SCORING: Journal article
C2 - 26580221
VL - 10
SP - e0142318
JO - PLOS ONE
JF - PLOS ONE
SN - 1932-6203
IS - 11
ER -