Immunomodulation through inhibition of multiple adhesion molecules generates resistance to autoimmune diabetes in NOD mice.
The effect of simultaneous blockade of adhesion molecules on the development of long-term resistance to type 1 diabetes was investigated in an adoptive transfer model in NOD mice. Splenocytes isolated from acutely diabetic NOD mice injected into NOD-scid mice caused diabetes at 43 +/- 5.0 days. Treatment with anti-alpha4-integrin monoclonal antibody (mAb) delayed the onset of insulitis and significantly delayed hyperglycemia to 66 +/- 5.8 days. Combination treatment with anti-alpha4-integrin and anti-LFA-1 mAbs delayed the onset of diabetes to >100 days (p<0.0001). Combination-treated mice were subjected to a second challenge with diabetogenic splenocytes after 85 days of normoglycemia. Without additional mAb treatment they developed hyperglycemia after significant delay (72 +/- 8.1 days post-reinoculation). Splenocytes from combination-treated mice transferred protection from diabetes to naive NOD-scid mice when co-transferred with diabetogenic splenocytes. The long-surviving mice showed periislet infiltration with CD62L+ cells, which were not seen in the insulitis developing in control animals. These findings suggest that adhesion molecule blockade does not prevent homing and may affect effector cell action through activation of immunoregulatory suppressor cells, leading to protection against development of diabetes.
Ninova
Dora
D
Transplantation Immunology Research Laboratory, Division of Transplantation, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA. ninova.dora@mayo.edu
Dean
Patrick G
PG
Stegall
Mark D
MD
D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000627:therapeutic use; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017690:Cell Transplantation; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D005260:Female; D007150:Immunohistochemistry; D007167:Immunotherapy; D039441:Integrin alpha4 / Q000276:immunology / Q000378:metabolism; D007515:Islets of Langerhans / Q000276:immunology / Q000473:pathology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology / Q000378:metabolism; D008214:Lymphocytes / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D014180:Transplantation; D016896:Treatment Outcome
D000906:Antibodies; D015815:Cell Adhesion Molecules; D016169:Lymphocyte Function-Associated Antigen-1; D039441:Integrin alpha4