Enhanced tumor necrosis factor in anti-CD3 antibody stimulated diabetic NOD mice: modulation by PGE1 and dietary lipid.
Administration of OKT3 anti-CD3 monoclonal antibody (mAb) to patients for transplant rejection, is associated with a distinct and often severe clinical syndrome related to massive cytokine release. Previous reports have similarly demonstrated increased levels of serum tumor necrosis factor alpha (TNF alpha) in normal mice following administration of 1452-C11 anti-CD3 mAb. In this study, we compared serum TNF alpha levels at baseline and after anti-CD3 stimulation among three groups of mice: normal BALB/c controls, pre-diabetic non-obese diabetic (NOD) mice, and diabetic NOD mice. Baseline serum TNF alpha levels, as measured by L929 cell bioassay, were 2xhigher in diabetic NOD and 3xhigher in pre-diabetic NOD compared with BALB/c. Ninety minutes after anti-CD3 mAb stimulation, serum from BALB/c controls and pre-diabetic NOD contained 2- to 8-fold higher levels of TNF-alpha as compared to untreated control mice. In contrast, following anti-CD3 mAb, there was a dramatic 20-fold increase in serum TNF alpha in diabetic NOD mice (levels > 5000 pg/ml). Additionally, anti-CD3 mAb increased the steady-state TNF alpha mRNA transcripts. Spleens from diabetic mice given anti-CD3 mAb had higher steady-state TNF alpha mRNA than spleen from normal mice similarly treated. The enhanced release of circulating TNF alpha after anti-CD3 mAb in diabetic NOD mice was abrogated by pre-treatment of mice with prostaglandin E1 (PGE1) 30 min prior to anti-CD3 mAb stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)
Barel
D
D
Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115.
Brennan
D C
DC
Jevnikar
A M
AM
Bastos
M
M
Strom
T B
TB
Kelley
V R
VR
D000527:Alprostadil / Q000494:pharmacology*; D000818:Animals; D001327:Autoimmune Diseases / Q000097:blood*; D017252:CD3 Complex / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000097:blood*; D004041:Dietary Fats / Q000494:pharmacology*; D005260:Female; D005395:Fish Oils / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C / Q000097:blood; D016688:Mice, Inbred NOD / Q000097:blood* / Q000276:immunology; D016853:Muromonab-CD3 / Q000494:pharmacology*; D012450:Safflower Oil / Q000494:pharmacology; D013047:Specific Pathogen-Free Organisms; D013154:Spleen / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis* / Q000096:biosynthesis / Q000378:metabolism
D017252:CD3 Complex; D004041:Dietary Fats; D005395:Fish Oils; D007166:Immunosuppressive Agents; D016853:Muromonab-CD3; D014409:Tumor Necrosis Factor-alpha; D012450:Safflower Oil; D000527:Alprostadil