Do vascular addressins mediate tissue specific lymphocyte extravasation?

In 1964, Gowans and Knight’ first described ‘the route of recirculation of lymphocytes in the rat. By using cells labelled with radioisotopes, they showed that small lymphocytes continuously recirculate between the blood and the lymph; extravasating via high endothelial venules (HEVs) into lymphoid tissues, then draining into lymphatics and reentering the blood via the thoracic duct. In addition, they demonstrated that many of the large dividing cells in the thoracic duct lymph (which receives its largest contribution from the intestinal lymphatics) extravasated into the lamina propria of the small intestine after being injected intravenously into syngeneic recipients. Since these observations, the complexity of lymphocyte migration has been demonstrated by an expanding literature on the subject. The migratory pathways of lymphocytes depend on whether they are large dividing or small quiescent cells; whether the cells are from lymph node, spleen, or lymph; whether they originate in the gut-associated lymphoid tissue (GALT) or the peripheral somatic lymphoid tissue (PSLT); and whether the cells being studied are B or T cells. In a recent publication,’ endothelial molecules believed to be involved in lymphocyte extravasation into the mucosae have been described. These molecules, the putative ‘vascular addressins’, communicate the site of the appropriate endothelium to recirculating lymphocytes, resulting in tissue specific extravasation. The existence of such vascular addressins is important not only in the understanding of the physiology of lymphocyte traffic, but by manipulating such molecules it may be possible to engineer tissue specific immunosuppression or to control the metastasis of lymphoid tumours. Before discussing the evidence for the existence of these molecules, it is worth reviewing briefly the results of some key studies of lymphocyte migration in vivo. Small lymphocytes from either mesenteric lymph node or peripheral somatic lymph nodes of rats,3 mice,4 and sheep,5 labelled in vitro and returned intravenously to syngeneic or autochthonous recipient animals, migrate randomly. Small lymphocytes from the lymph of adult sheep, however, show differential migration between GALT and PSLT.6 Technically, these experiments require that both an intestinal lymphatic and an efferent lymphatic from a peripheral somatic lymph node be cannulated. It can then be demonstrated that small lymphocytes obtained from intestinal lymph, when radiolabelled in vitro and returned intravenously to the same animal, preferentially re-enter the intestinal lymph. Similarly, if cells from the efferent lymphatic of a peripheral somatic node are collected, labelled in vitro, and returned intravenously to the same sheep, the cells will tend to reappear in the lymph from the peripheral somatic node. It is not possible to compare the migratory characteristics of lymph-borne small lymphocytes from the intestine and peripheral nodes in rats and mice because it is not possible to collect intestinal lymph and lymph from a peripheral somatic lymph node of the same animal simultaneously. Small B lymphocytes from mesenteric or peripheral lymph node or thoracic duct lymph may preferentially extravasate into the Peyer’s patches in short-term adoptive transfer experiments (less than 1 h after intravenous injection) in mice7 and rats. ’ There are, however, several problems in interpreting these data. Firstly, using thoracic duct lymph of nude rats as a source of B cells for adoptive transfer, Fossum et a1. ’ showed that the short-term migratory behaviour of B cells is particularly susceptible to changes in behaviour caused by reduction in temperature during handling. Short-term storage at low temperatures reduces B cell extravasation into PSLT in particular. This may explain the apparently preferential localization of B cells in the Peyer’s patches, the site least susceptible to temperature-induced changes in the B cells. Secondly, after 24 h there is no differential distribution of B and T cells irrespective of their source between the Peyer’s patches and the lymph nodes. ’ Thirdly, the