The thymus as a site for evaluating the potency of candidate beta cell autoantigens in NOD mice.
Intrathymic (i.t.) injection of islet cells or whole islets retards development of insulin dependent diabetes mellitus (IDDM) in spontaneous animal models of the disease. Protection of 4-week-old prediabetic NOD/Lt female mice from subsequent IDDM development was specific for the it route of administration since intraperitoneal injection of an equal number of syngeneic islets failed to retard IDDM. The protective effect of i.t. injection of islet cells was compared with the effect of i.t. injection of syngeneic peritoneal exudate cells, NIT-1 cells, bovine serum albumin (BSA), ABBOS peptide, a 52 kDa islet cell membrane protein, various synthetic peptides from human glutamic acid decarboxylase (GAD) and a Coxsackievirus B4-derived peptide with homology to GAD. Interestingly, only a GAD-derived peptide containing sequence homology to Coxsackie-virus B4, and the corresponding Coxsackievirus B4-derived peptide, delayed IDDM onset. To establish the immunological mechanism underlying the reduced IDDM incidence following i.t. injection of islet cells, adoptive transfer of splenic leukocytes into NOD-scid/scid mice was performed. Splenic leukocytes from i.t.-injected non-diabetic females transferred IDDM into NOD-scid/scid recipients, but more slowly than splenocytes from unmanipulated, diabetic (control) donors. Co-transfer of 1:1 mixtures of splenic leukocytes from it islet-injected (and diabetes-free) NOD/Lt females and from untreated NOD/Lt diabetic donors produced IDDM as rapidly as splenocytes from diabetic donors injected alone. Hence, any peripheral suppression generated in i.t.-protected females was not sufficiently strong to prevent IDDM transfer by committed T-effector cells from the diabetic donors.(ABSTRACT TRUNCATED AT 250 WORDS)
Gerling
I C
IC
Jackson Laboratory, Bar Harbor, ME 04609.
Atkinson
M A
MA
Leiter
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EH
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000595:Amino Acid Sequence; D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D005069:Evaluation Studies as Topic; D005260:Female; D005968:Glutamate Decarboxylase / Q000276:immunology*; D007116:Immunization, Passive; D007515:Islets of Langerhans / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D008969:Molecular Sequence Data; D011506:Proteins / Q000276:immunology; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013950:Thymus Gland / Q000276:immunology*
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D011506:Proteins; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D005968:Glutamate Decarboxylase