Transfusion of nonobese diabetic mice with allogeneic newborn blood ameliorates autoimmune diabetes and modifies the expression of selected immune response genes.
Although allogeneic bone marrow transplantation has been shown to prevent autoimmune diabetes in heavily irradiated nonobese diabetic (NOD) mice, a similar procedure is not suitable for the treatment of patients with type 1 diabetes because of associated severe side effects. Therefore, we evaluated whether mouse newborn blood (NBB), equivalent to human umbilical cord blood, could be used for diabetes prevention without recipient preconditioning. To test this hypothesis, unconditioned, prediabetic female NOD mice were given a single injection of whole NBB derived from the allogeneic diabetes-resistant mouse strain C57BL/6. Transfusion of allogeneic NBB but not adult blood prevented diabetes incidence in a majority of treated mice for a prolonged period of time. This was accompanied by the release of insulin in response to a challenge with glucose. Invasive cellular infiltration of islets was also substantially reduced in these mice. Although NBB transfusion induced a low level of hematopoietic microchimerism, it did not strictly correlate with amelioration of diabetes. Induction of genes implicated in diabetes, such as Il18, Tnfa, and Inos but not Il4, Il17 or Ifng, was repressed in splenocytes derived from protected mice. Notably, expression of the transcription factor Tbet/Tbx21 but not Gata3 or Rorgt was upregulated in protected mice. These data indicate that allogeneic NBB transfusion can prevent diabetes in NOD mice associated with modulation of selected cytokine genes implicated in diabetes manifestation. The data presented in this study provide the proof of principle for the utility of allogeneic umbilical cord blood transfusion to treat patients with autoimmune diabetes.
Jayaraman
Sundararajan
S
Department of Surgery, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA. anue2468@uic.edu
Patel
Tejas
T
Patel
Vasu
V
Ajani
Shahnaz
S
Garza
Rebecca
R
Jayaraman
Arathi
A
Kwon
Sung
S
Singh
Rajvir
R
Rondelli
Damiano
D
Prabhakar
Bellur S
BS
Holterman
Mark
M
D000818:Animals; D000831:Animals, Newborn; D000950:Antigens, Ly / Q000096:biosynthesis / Q000235:genetics; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D005260:Female; D005312:Fetal Blood / Q000166:cytology / Q000276:immunology / Q000637:transplantation*; D020022:Genetic Predisposition to Disease; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology; D016130:Immunophenotyping; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D011236:Prediabetic State / Q000235:genetics / Q000276:immunology / Q000473:pathology
D000950:Antigens, Ly; D016207:Cytokines; D018836:Inflammation Mediators; C074650:Ly6a protein, mouse; D008565:Membrane Proteins