THE IMMUNOSUPPRESSIVE MECHANISM OF TOTAL LYMPHOID IRRADIATION

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Abstract
Total lymphoid irradiation is an effective immunosup-pressive therapy used to prepare patients for organ transplantation and to treat several autoimmune diseases. We have used the mouse model to investigate the mechanism of TLI-induced immunosuppression. Mice were irradiated with 250-rad daily fractions to a total dose of 3500 rads. Splenocytes from control and TLI-treated mice were analyzed for IL-2 production, IL-2 receptor expression after mitogen stimulation, and percent L3T4 positive cells. At two weeks following the completion of TLI, IL-2 production from whole spleen populations had decreased 90% compared with controls (TLI mean IL-2 units = 25±9.0, control mean = 277± 104). IL-2 receptor expression on splenocytes following Con A stimulation was decreased 80% compared with controls (TLI mean percentage of IL-2 receptor expressing cells = 16.2±4.1, control mean = 82.0±7.5). L3T4+ cells that expressed IL-2 receptor were also decreased following TLI (TLI mean = 4.4±1.4, control mean = 22.0±3.8), as were proliferative responses to Con A and PHA. Addition of recombinant mouse IL-2 did not restore IL-2 receptor expression or proliferative responses. Whole TLI-treated splenocytes did not suppress IL-2 production or proliferative responses of normal splenocytes. These immunologic abnormalities recovered over time, and by 8 weeks post TLI IL-2 production, IL-2 receptor expression, L3T4+ cell numbers and proliferative responses had returned toward normal. These results suggest that TLI therapy transiently depletes IL-2 producing, IL-2 receptor expressing, and mitogen responsive lymphocytes. The immunosuppression is not mediated through a suppressor cell and is independent of IL-2 production.

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