The development of experimental autoimmune encephalomyelitis in the mouse requires alpha4-integrin but not alpha4beta7-integrin.

Abstract

Because monoclonal antibodies (mAbs) directed against ␣ 4-integrin and VCAM-1 inhibit the development of experimental autoimmune encephalomyelitis (EAE) in vivo, it has been concluded that the successful therapeutic effect is due to interference with ␣ 4 ␤ 1/VCAM-1-mediated interaction of autoaggressive T cells with the blood-brain barrier. A possible role for ␣ 4 ␤ 7-integrin, or interference with other T cell mediated events during the pathogenesis of EAE, has not been considered. We have compared the effects of mAb therapy on the development of EAE in the SJL/N mouse, using a large panel of mAbs directed against ␣ 4, ␤ 7, the ␣ 4 ␤ 7-heterodimer, and against VCAM-1. Although encephalitogenic T cells express both ␣ 4-integrins, mAbs directed against the ␣ 4 ␤ 7-heterodimer or against the ␤ 7-subunit did not interfere with the development of EAE. In contrast, mAbs directed against ␣ 4 and VCAM-1 inhibited or diminished clinical or histopathological signs of EAE. Our data demonstrate for the first time that ␣ 4 ␤ 7 is not essential for the development of EAE.

E- and P-Selectin Are Not Required for the Development of Experimental Autoimmune Encephalomyelitis in C57BL/6 and SJL Mice

“…In fact, as we and others have previously demonstrated that ␣ 4 integrins are involved in T cell activation (6,26), some other ␣ 4 integrin-dependent pathomechanisms entirely independent of leukocyte trafficking may contribute to the therapeutic success of targeting ␣ 4 integrins in EAE. Alternatively, one may question the relevance of leukocyte trafficking across superficial brain vessels for EAE pathogenesis.…”

“…In contrast, it has been shown that targeting leukocyte trafficking into the CNS by blocking ␣ 4 integrins blocks CNS inflammation and clinical EAE in a number of EAE models in SJL mice (3,6), rats (2), and guinea pigs (5). Intravital microscopy studies have confirmed that ␣ 4 integrins contribute to rolling (8) and firm adhesion (9) of endogenous leukocytes in superficial mouse brain vessels during EAE in the C57BL/6 mouse.…”

“…After the seminal study by Yednock et al (2) demonstrating that Abs blocking ␣ 4 integrin inhibit EAE by blocking T cell interaction with the BBB, numerous following studies confirmed and extended the predominant involvement of ␣ 4 integrin/VCAM-1 in inflammatory cell recruitment into the CNS in different EAE models in a number of species (3)(4)(5)(6). Using intravital microscopy, we have demonstrated that the recruitment of encephalitogenic T cell blasts across the spinal cord white matter microvasculature in healthy mice depends on ␣ 4 integrin-mediated initial capture and G protein-dependent arrest (7).…”

Migration of immature mouse DC across resting endothelium is mediated by ICAM‐2 but independent of β2‐integrins and murine DC‐SIGN homologues

“…The murine epidermal DC progenitor line XS52 [21,22] and the proteolipid protein (PLP)-specific T helper 1 memory/ effector T cell line SJL.PLP7 [46] have previously been described in detail. Three endothelioma cell lines were used: wild-type bEnd.5, bEndI1/2.1 (ICAM-1 -/ICAM-2 -), bEndI1/ 2.1-ICAM1 (ICAM-1 + /ICAM-2 -) and bEndI1/2.1-ICAM2 (ICAM-1 -/ICAM-2 + ).…”

PSGL‐1 and E/P‐selectins are essential for T‐cell rolling in inflamed CNS microvessels but dispensable for initiation of EAE

“…Agspecific restimulation, measurement of T-cell proliferation by 3 H-thymidine incorporation, and long-term culture of the PLPspecific T-cell lines were performed exactly as previously described [14,33]. Both T-cell lines were cultured for at least three rounds of PLP aa139-151 -specific stimulation prior to the IVM experiments. …”