EXPRESSION OF A PROTECTIVE INTESTINAL IMMUNE-RESPONSE CAN BE INHIBITED AT 3 DISTINCT SITES BY TREATMENT WITH ANTI-ALPHA-4 INTEGRIN

The alpha4 integrins mediate lymphocyte adhesion to Peyer's patch high endothelial vessels and homing to Peyer's patch, as well as to mesent eric lymph nodes. In rats, immunity to infection with the nematode Tri chinella spiralis is known to be mediated by CD4+ OX22- (CD45RC-) cell s that home to the intestine in large numbers. These experiments were conducted to determine whether the alpha4 integrins or LFA-1 were invo lved in the expression of intestinal immunity to T spiralis. Injection of the anti-alpha4 integrin, mAb TA-2, but not anti-LFA-1, mAb TA-3, impaired the expression of immunity. An effect of TA-2 was measured at three distinct sites along the activation pathway leading to the migr ation of protective CD4+ OX22- cells to the intestine. Injection of TA -2 on the same day as infection prevented normal rejection of the para site and abrogated the characteristic appearance of blast cells in dra ining lymph 3 days after infection. A similar effect on the migration of blast cells at day 3 was seen when TA-2 was injected 1 day after in fection, and injection 2 days after infection still reduced the number of protective cells entering TD lymph on day 3. The effect of TA-2 an d TA-3 on homing of dividing cells to the gut was examined by injectin g dividing cells i.v. at the same time as antibody. Under these condit ions migration of dividing cells to the gut was reduced by 90 to 95% a nd their capacity to adoptively transfer worm rejection blocked. Furth ermore, TA-2 treatment also inhibited protection when it was injected 12, 18, or 24 h after the transfer of protective cells, when these cel ls had already entered the gut, but not when TA-2 injection was delaye d for 36 h. These results indicate the involvement of alpha4 integrins at the following points in the generation, dissemination, and functio n of CD4+ OX22- effectors: 1) initial activation during the first 48 h of infection; 2) migration of protective cells to and extravasation i n the gut; 3) a function after entry into gut tissues. The results sug gest that entry of dividing cells into the gut is critical for the ado ptive transfer of protection and that alpha4 integrin has multiple rol es in the manifestation of intestinal immunity.