703 Gut-Homing CD4+ Lymphocytes Are Specifically Targeted in Cynomolgus Monkeys Dosed with Anti-Beta7 Antibodies (original) (raw)

role of Ucns and CRF receptors in GI diseases is unclear. Aim: To evaluate the contribution of CRFR2 to inflammation, using a murine model of Crohn's colitis, and to test whether Ucn1 exerts its anti-inflammatory effects via CRFR2. Methods: An intracolonic enema of trinitrobenzene sulfonic acid (TNBS) was used to induce colitis in male C57 mice. An enema of vehicle was given to control group. First, the effect of TNBS was evaluated on the mortality rate and severity of colitis in wild type mice (Wt), CRFR2-/-(KO), and CRFR2+/-(Ht) mice. Second, Ucn1 was given (ip) when TNBS colitis was induced, to test whether Ucn1 could still exert its anti-inflammatory effects and ameliorate colitis in CRFR2 KO mice. Results: At a 5 mg dose of TNBS, resultant colitis in Wt C57 mice caused a~20% mortality rate 2 days after injection of TNBS. Surprisingly, 5 mg of TNBS did not cause any mortality in CRFR2-/-KO mice. In contrast, TNBS resulted in over 60% mortality rate within 3 days of TNBS injection in CRFR2+/-micE. colitis resulted in marked shortening of colon length in from 8.4±0.16 cm (controls) to 6.1±0.27 cm, p<0.05 (Wt), and the length was further shortened in KO and Ht mice to 5.6±0.2 cm. Adrenals were hypertrophied in mice with colitis, weighing twice as much as control adrenals. Colitis significantly increased histologic damage seen in H&E stained colon tissue of Wt and CRFR2 KO or Ht mice. Ucn 1 injection did not alter the mortality rate in Wt or KO mice with colitis, whereas Ucn1 dramatically rescued CRFR2+/-mice with colitis; none died until the experiment ended. This increase in survival rate was accompanied by significant improvement in colon histology as seen in H&E stained sections from CRFR2+/-mice. MPO levels were significantly decreased in Wt and Ht mice treated with Ucn1+TNBS (1.53±0.3 and 2.4±0.9 mU/mg) compared with KO Ucn1+TNBS mice (7.9±1.9 mU/mg, p<0.05). Interestingly, adrenal weights of CRFR2+/mice treated with Ucn1 were comparable to control levels, whereas adrenal weights remained elevated in Wt and KO mice treated with Ucn1. Conclusions: Perturbations in the CRFR2 receptor expression levels dramatically alter mice' ability to handle acute inflammatory stress. Complete lack of CRFR2 probably results in major developmental compensatory changes that enable the KO mice to better survive acute inflammatory stress. Supported in part by Hellman Foundation award to AB.