Vascular addressins are induced on islet vessels during insulitis in nonobese diabetic mice and are involved in lymphoid cell binding to islet endothelium.

Abstract

In the nonobese diabetic (NOD) mouse, lymphocytic and monocytic infiltration of the pancreatic islets leads to beta cell destruction. To investigate the mechanisms by which lymphocytes enter the NOD pancreas, pancreata were immunostained using monoclonal antibodies to a variety of adhesion molecules known to be involved in lymphocyte binding to vascular endothelium, an initial step in the migration of lymphocytes from blood into organized lymphoid and inflamed tissues. These adhesion molecules include: lymphocyte homing receptors involved in tissue-selective binding of lymphocytes to peripheral lymph node (L-selectin) or mucosal lymphoid tissue (LPAM-1, a437-integrin) high-endothelial venules (HEV); and HEV ligands peripheral vascular addressin (PNAd) and mucosal vascular addressin (MAdCAM-1). In NOD pancreata, a4#7 is expressed on most infiltrating cells at all stages of insulitis, whereas L-selectin expression is more pronounced on cells in the islets at later stages. During the development of insulitis, MAdCAM-1 and to a lesser extent PNAd became detectable on vascular endothelium adjacent to and within the inflamed islets. The Stamper-Woodruff in vitro assay was used to examine lymphoid cell binding to such vessels. These functional assays show that both the mucosal (MAdCAM-1 /a47) and the peripheral (PNAd/L-selectin) recognition systems are involved in this binding. Our findings demonstrate that expression of peripheral and mucosal vascular addressins is induced on endothelium in inflamed islets in NOD pancreas, and that these addressins participate in binding lymphoid cells via their homing receptors. This suggests that these adhesion molecules play a role in the pathogenesis of diabetes in these mice by being involved in the migration of lymphocytes from blood into the inflamed pancreas. (J. Clin. Invest. 1993. 92:2509-2515

Longitudinal three-dimensional visualisation of autoimmune diabetes by functional optical coherence imaging

“…8e-g, j). This supports previous observations of lymphocyte-HEV recognition in the development of insulitis in NOD mice [8,15,32,33]. Interestingly, a similar distribution of CD31 + vs HEVs was also seen in inflamed ACEtransplanted NOD islets (Fig.…”

Homing of human autoreactive T cells into pancreatic tissue of NOD-scid mice

“…Mucosal lymphoid organs preferentially express MAdCAM-1 on high endothelial venules [28]. MAdCAM-1 is also expressed in inflamed islets of NOD mice and human diabetic pancreas [29,30] and was shown to mediate pancreatic homing of murine T cells [31]. In prediabetic mice, MAdCAM-1 is constitutively expressed in the exocrine tissue and on vessels adjacent to but not inside the islets [32].…”

L-Selectin Is Not Required for T Cell-Mediated Autoimmune Diabetes

“…First, as suggested by the work of Dobbs and Haskins (38), redundancy in pancreatic migration mechanisms may permit the recruitment of T cells in the absence of CD62L-mediated interactions. During development, pancreatic tissue derives partially from the mesoderm as does the intestine (18,39) and consequently shares adhesion properties with the mucosa. The ␣ 4 ␤ 7 integrin ligand MAdCAM-1 is constitutively expressed in the exocrine pancreas (18) and is detected in the islets during inflammation (20).…”

“…During development, pancreatic tissue derives partially from the mesoderm as does the intestine (18,39) and consequently shares adhesion properties with the mucosa. The ␣ 4 ␤ 7 integrin ligand MAdCAM-1 is constitutively expressed in the exocrine pancreas (18) and is detected in the islets during inflammation (20). Because pancreatic lymph node cellularity was not significantly affected by the absence of CD62L (Table I and Fig.…”

“…Because treatment with MEL-14 mAb does not deplete lymphocytes in vivo or suppress T cell responses against ␤ cell autoantigens (18,20), it is possible that early Ab treatment during the first 4 wk of life induces a form of immunoregulation preventing the establishment of insulitis (18). This regulation may involve the activation and/or expansion of a recently identified subset of regulatory T cells bearing a CD4 ϩ CD25 ϩ CD62L high phenotype and capable of preventing the adoptive transfer of diabetes (47,48).…”