MULTIPLE LOW-DOSE STREPTOZOCIN-INDUCED DIABETES IN NOD-SCID SCID MICEIN THE ABSENCE OF FUNCTIONAL LYMPHOCYTES/

The murine severe combined immunodeficiency (scid) mutation was used t o assess whether the diabetogenic effects of multiple low-dose strepto zocin (MD-STZ) administration required the presence of functional T-ce lls. An STZ dose as low as 30 mg/kg body wt for 5 days induced hypergl ycemia in young NOD/Lt-+/+ male mice, whereas a dose of 50 mg/kg for 5 days was required to elicit comparable hyperglycemia in C.B.-17-+/+ m ale mice. The greater NOD strain sensitivity was not a function of pre existing insulitis, because insulitis- and diabetes-free NOD male mice congenic for a diabetes-resistant major histocompatibility complex ha plotype were equally susceptible to MD-STZ. This was confirmed in NOD- scid/scid and C.B.-17-scid/scid males. Both were completely insulitis- free, and despite the absence of functional T-cells and B-cells, both congenic stocks were as sensitive to MD-STZ as congenic +/+ controls. Indeed, MD-STZ-induced hyperglycemia in NOD-scid/scid male mice was si gnificantly higher than in NOD/Lt-+/+ male mice. The NOD-scid/scid mou se as a recipient of adoptively transferred splenocytes clearly deline ated a distinct pathogenesis of spontaneous insulin-dependent diabetes mellitus (IDDM) versus MD-STZ-induced hyperglycemia. Splenocytes from spontaneously diabetic NOD/Lt males, but not those from donors given MD-STZ, readily transferred IDDM, even when host beta-cells were sensi tized by a single injection of Sh before adoptive transfer. We conclud e that IDDM induced by MD-STZ is not mediated by T-cell-or B-cell-depe ndent autoimmune mechanisms in a fashion analogous to the spontaneous IDDM characteristic of NOD mice.