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 de velopment of insulin dependent diabetes mellitus' (IDDM) in spontaneou s animal models of the disease. Protection of 4-week-old prediabetic N OD/Lt female mice from subsequent IDDM development was specific for th e it route of administration since intraperitoneal injection of an equ al number of syngeneic islets failed to retard IDDM. The protective ef fect of i.t. injection of islet cells was compared with the effect of i.t. injection of syngeneic peritoneal exudate cells, NIT-1 cells, bov ine serum albumin (BSA), ABBOS peptide, a 52 kDa islet cell. membrane protein, various synthetic peptides from human glutamic acid decarboxy lase (GAD) and a Coxsackievirus B4-derived peptide with homology to GA D. Interestingly, only a GAD-derived peptide containing sequence homol ogy to Coxsackievirus B4, and the corresponding Coxsackievirus B4-deri ved peptide, delayed IDDM onset. To establish the immunological mechan ism underlying the reduced IDDM incidence following i.t. injection of islet cells, adoptive transfer of splenic leukocytes into NOD-scid/sci d mice was performed. Splenic leukocytes from i.t.-injected non-diabet ic females transferred IDDM into NOD-scid/scid recipients, but more sl owly than splenocytes from unmanipulated, diabetic (control) donors. C o-transfer of 1:1 mixtures of splenic leukocytes from it islet-injecte d (and diabetes-free) NOD/Lt females and from untreated NOD/Lt diabeti c donors produced IDDM as rapidly as splenocytes from diabetic donors injected alone. Hence, any peripheral suppression generated in i.t.-pr otected females was not sufficiently strong to prevent IDDM transfer b y committed T-effector cells from the diabetic donors. Studies in prog ress suggest that it exposure to islet cell autoantigens mediates IDDM protection by retarding the activation of islet autoreactive effector cells. In summary, although the mechanisms underlying IDDM retardatio n by introduction of islet cell autoantigens into the thymic micro-env ironment are not well understood, the method provides a useful bioassa y for establishing the specific pathogenic potential of 'candidate' is let autoantigens.