In vitro studies have revealed several pathways by which T cells can respond to alloantigens, including CD4+ direct responses to allogeneic class 11 antigens, CD8+ direct responses to allogeneic class I antigens, and CD4+ "indirect" responses to peptides of alloantigens presented in association with responder class 11 molecules. In vivo studies of skin graft rejection, however, have so far provided dear evidence for the contribution of only the two direct pathways and not for indirect recognition. We have used major histocompatibility complex class 11-deficient mice as donors to test the role of indirect recognition in rejection of skin grafts. Class 11-deficient skin was always rejected without delay by normal recipients. Removal of recipient CD8+ cells (to leave the animals dependent on CD4+ function) or depletion of recipient CD4+ cells revealed that CD4+ cells were usually involved and sometimes absolutely required in this rapid rejection. Since the donor grafts lacked class II antigens, the CD4+ cells must have recognized donor antigens presented in association with recipient class 11 molecules. These results therefore indicate that indirect recognition can initiate rapid skin graft rejection.Theories to explain the special importance of major histocompatibility complex (MHC) antigens in graft rejection and the extraordinary strength of the immune response to these antigens are all based on the capacity of T cells to recognize allogeneic MHC antigens directly without the usual requirement that their peptides be processed and presented by recipient antigen presenting cells (APCs) (1-3). As a result, studies of the mechanisms of graft rejection have been dominated by concern with the direct pathways of alloreactivity. A few investigators, however, have considered the possibility that graft rejection might also occur through more classical immunologic mechanisms in which peptides of donor antigens are presented in association with recipient MHC molecules. La Rosa and Talmage (4) described this possibility as "indirect" recognition, but the actual role of this pathway in graft rejection has been difficult to determine.Recently, "knockout" mice lacking MHC class II antigens have been produced by the technique of targeted gene disruption by homologous recombination in embryonic stem cells (5, 6). Since these mice lack the MHC class II antigens responsible for stimulating CD4+ T cells, grafts from these mice can be used to examine rejection in the absence of direct stimulation of these helper T cells. The experiments described in this report suggest that in the absence of donor class II antigens, indirect recognition remains an effective pathway of alloreactivity leading to rapid graft rejection. MATERIALS AND METHODSClass II-Deficient Mice. The development and initial characterization of the class II-deficient mice used in these experiments have been described (5). Briefly, the Apb gene was disrupted in the D3 embryonic stem cell line of 129/Sv origin by the technique of homologous recombination. Cloned e...
After ischemia and reperfusion, severe alterations in the cytoskeletal organization of renal tubular epithelial cells have been reported. These effects, accompanied by a modification in the polarized distribution of some membrane transport proteins, are especially evident in the proximal tubule. In normal proximal tubule cells, actin is concentrated in apical brush border microvilli, along with the actin-binding protein villin. Because villin plays an important role in actin bundling and in microvillar assembly but can also act as an actin-fragmenting protein at higher calcium concentrations, we examined the effects of ischemic injury and reperfusion on the distribution of villin and actin in proximal tubule cells of rat kidney. Using specific antibodies against villin and actin, we show that these proteins redistribute in parallel from the apical to the basolateral plasma membrane within 1 h of reperfusion after ischemia. Ischemia alone had no effect on the staining pattern. Repolarization of villin to the apical membrane begins within hours after reperfusion with enhanced apical localization over time during the period of regeneration. This apical repolarization of villin is accompanied by the migration of actin back to the apical membrane. These results show not only that villin may be involved in the initial disruption of the actin cytoskeleton during reperfusion injury but also that its migration back to the apical domain of these cells accompanies the reestablishment of a normal actin distribution in the brush border.
RAL bladder augmentation can be safely and efficiently performed. There is a rapid learning curve. We identified minor technical modifications in techniques to help reduce operative time and potential complications. We recommend performing the bowel-bowel anastomosis outside the peritoneum to avoid the risk of leakage. Leakage at the bowel-bladder anastomosis may occur but can be managed with simple catheter drainage.
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