ELEVATED SERUM LEVELS OF MACROPHAGE-DERIVED CYTOKINES PRECEDE AND ACCOMPANY THE ONSET OF IDDM

To determine whether cytokines could have a role in the development of insulin-dependent diabetes mellitus (IDDM), we measured serum levels of cytokines derived from T helper 1 (interleukin-2 and interferon-gam ma), T helper 2 (interleukin-4 and interleukin-10) lymphocytes and mac rophages (tumour necrosis factor-alpha, interleukin-1 alpha and interl eukin-1 beta) in patients before and after the onset of IDDM. Recently diagnosed IDDM patients had significantly higher levels of interleuki n-2, interferon-gamma, tumour necrosis factor-alpha and interleukin-1 alpha than patients with either long-standing IDDM, non-insulin-depend ent diabetes (NIDDM), Graves' disease, or control subjects (p < 0.05 f or all). Compared with control subjects, patients with long-standing I DDM and those with NIDDM had higher interleukin-2 and tumour necrosis factor-alpha levels (p < 0.01 for all). Interleukin-4 and interleukin- 10 were detectable in sera of patients with Graves' disease only, whil e interleukin-1 beta was not detectable in the serum of any control or test subject. To investigate whether high cytokine levels precede the onset of IDDM, we studied 28 non-diabetic identical co-twins of patie nts with IDDM, followed-up prospectively for up to 6 years after the d iagnosis of the index. Levels of tumour necrosis factor-alpha and inte rleukin-1 alpha were elevated above the normal range more frequently i n the eight twins who developed diabetes than in those 20 who did not (p < 0.005). Analysis of T helper 1 and T helper 2 profiles of the twi n groups did not reveal a clear difference between prediabetic twins a nd twins remaining non-diabetic. These results support the notion that T helper 1 lymphocytes may play a role in the development of IDDM. Th is is associated with release of macrophage-derived cytokines, which i s also a feature of the prediabetic period. The lack of evidence of a dominant T helper 1 profile of cytokine release before diabetes onset suggests that additional events, activating this arm of the cellular i mmune response, are required in the immediate prediabetic period.