Immunohistochemical findings, idiotypic inhibition and clinical outcome in patients developing donor-specific antibodies after kidney transplantation.
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Biomedical subjects
Publications and source records attributed to U T Hopt.
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CMV-infections are a common and dreadful complication in immunosuppressed patients after kidney transplantation. This randomized, controlled clinical study investigates the influence of CMV-hyperimmune serum (HIS)-prophylaxis on infection incidence and severity of illness with regard to the type of immunosuppression employed. Though the clinical manifestation of the disease is lowered by HIS in cyclosporin-treated patients, there is a higher infection incidence with increased severity in HIS-treated ATG/Imurek patients compared to the respective control.
Very high mortality rates are encountered in emergency gastric operations in the aged. In contrast, elective surgery is associated with a low mortality rate. The outcome is strongly influenced by concomitant diseases. Timing of operation is crucial in aged patients with gastrointestinal ulcer.
The recruitment of indium-111-labeled unsensitized lymphocytes (ULs) from the circulation into healed subcutaneous urethane sponge implants inoculated with specifically sensitized T lymphocytes (SSLs) and allogeneic target cells was studied in mice. Intravenously injected ULs were preferentially recruited to the site of specific effector-target interaction. Preferential recruitment was demonstrable within 1 hr of i.v. injection and was maximal at 4 hr. The recruitment of ULs was proportional to the number of SSLs or targets injected into the sponge. Effector cells capable of mediating the recruitment of ULs when presented with the sensitizing alloantigenic cells are detectable early in mixed lymphocyte culture (MLC) prior to the development of strong cytotoxicity. Furthermore, effector cells can be generated in MLC between H-2 identical but Mls-disparate strains in which a proliferative response occurs, but few cytotoxic cells develop. Depletion of Lyt-2+ cells from day 5 MLC abrogates cytotoxicity, but the capacity of the remaining cells to mediate recruitment is not changed. In contrast, depletion of Lyt-1+ cells does not alter cytotoxicity, but significantly reduces recruitment mediated by the remaining sensitized cells. These results suggest that recruitment of circulating lymphocytes to the site of an allograft response is mediated by an immunologicaly specific interaction between SSLs and alloantigen. These SSLs may be proliferating noncytotoxic lymphocytes or cytotoxic T lymphocytes. The capacity of a specific immune interaction at the allograft site to recruit circulating lymphocytes may be a rapid and potentially important mechanism of immune amplification in allograft rejection.
The mechanisms responsible for the accumulation of lymphocytes in rejecting allografts may involve lymphokine-mediated changes in blood flow and vascular permeability. Changes in lymphocyte recruitment (LR), regional blood flow (RBF), and vascular permeability (VP) were studied in paired healed subcutaneous urethane sponge grafts inoculated with specifically sensitized lymphocytes (SSL) and allogeneic target cells. Intravenous injection of Indium-111-labeled unsensitized lymphocytes (UL), rubidium-86-chloride, and Iodine-125-labeled albumin was used to assess LR, RBF, and VP, respectively. An increase in LR (p less than 0.001), RBF (p less than 0.001), and VP (p less than 0.001) could be demonstrated at the site of interaction between specifically sensitized lymphocytes and targets bearing the sensitizing alloantigen. Lymphocyte recruitment, blood flow, and vascular permeability indexes were all elevated within 4 hr after graft inoculation, peaked at 8 hr, and declined at approximately the same rate over the subsequent 24 hr. RBF returned to baseline levels by 24 hr, whereas LR and VP remained elevated. Suspension of SSL and targets in dexamethasone acetate (1 x 10(-5) M) before graft inoculation completely inhibited the early increase in RBF, but only incompletely blocked LR and VP. At 24 hr, however, VP was almost totally inhibited and LR remained elevated. These results are consistent with the idea that the interaction between SSL and specific alloantigen in vivo leads to the rapid elaboration of lymphokines, which increases RBF and VP, in addition to the accumulation of circulating unsensitized cells. These vascular effects could partly be responsible for the heterogeneity and nonspecificity of the cellular infiltrate in rejecting allografts. Specific enrichment of the graft infiltrate with sensitized cells would require that other mechanisms be operative.
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The migration of indium-III-labeled specifically sensitized lymphocytes (SSLs) and unsensitized spleen lymphocytes (ULs) into sponge matrix allografts was studied in irradiated mice. Intravenously injected SSLs were preferentially recruited to the graft bearing the sensitizing alloantigen. High numbers of these SSLs, however, were attracted regardless of their immunological specificity to a third-party graft, when cells sensitized against the third-party antigen were given simultaneously. When SSLs were injected locally into a specific and third-party graft, i.v. injected ULs also homed preferentially to the specific graft. Prior treatment of SSLs with anti-theta serum and complement abrogated their cell recruiting capacity. The percentage of injected lymphocytes recruited to the specific allograft during the first 36 hr increased with the number of SSLs injected. The duration of augmented lymphocyte recruitment, however, was inversely related to the number of SSLs injected into the graft. Furthermore, there is some evidence that SSLs which have been recruited to an allograft migrate to a second site of antigen challenge and initiate there a high lymphocyte recruitment. These results suggest that increased lymphocyte recruitment to an allograft is initiated by an immunologically specific interaction between SSLs and alloantigen. The cells, however, which are preferentially recruited to an allograft, comprise small unsensitized lymphocytes and SSLs regardless of their immunological specificity. Lymphocytes with cell recruiting activity are T cells and appear to be very mobile in vivo. The mechanism described might have an important amplifying effect on allograft rejection.
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BACKGROUND: Ischemia-reperfusion injury has been shown to deteriorate microcirculation in experimental pancreas transplantation. However, minor concern was taken on the impact of organ procurement in this condition. We examined the impact of a standardized technique of organ procurement on microcirculation and apoptosis in experimental pancreas transplantation. METHODS: Male Lewis rats were divided into three groups: sham-operated animals without dissection of the pancreas served as controls (n = 5); animals undergoing nearly total process of organ procurement with the pancreas pedunculated on the aorta and the hepatoduodenal ligament (n = 7), and animals receiving pancreaticoduodenal transplantation. Pancreatic grafts were preserved for 6 h in cold University of Wisconsin solution (n = 7). At 1 and 2 h reperfusion and in time-matched controls, microcirculation was assessed by means of intravital fluorescence microscopy. Tissue samples were obtained after 2 h measurement and DNA breaks of acinar cells were detected by in situ nick end-labeling (TUNEL assay). The apoptotic index (apoptotic cells per high- power fields; hpf) was quantified by microscopic counting of at least 50 hpf. RESULTS: Assessment of functional capillary density (FCD) in animals undergoing subtotal process of organ procurement revealed a slight non-significant decrease at 1 and 2 h compared with controls. In addition, leukocyte sticking to postcapillary venules (LAV) as well as the apoptotic index were found slightly increased after organ procurement compared with controls (p > 0.05). However, after pancreas transplantation the apoptotic index and the LAV were significantly increased and the FCD significantly decreased compared with both groups of non-transplanted animals (p < 0.01). CONCLUSIONS: Our validated technique of organ procurement does not negatively impact microcirculation and apoptosis in experimental pancreas transplantation.
INTRODUCTION: In pancreatic ischemia/reperfusion (IR) injury (IRI) the role of nitric oxide (NO) is not completely understood. Using a rat model of normothermic in situ IRI, the effect of endogenous and exogenous NO donors on post-ischemic tissue oxygenation and tissue damage was investigated. METHODS: IR was induced by 2-hour normothermic in situ ischemia of a pancreatic tail segment pedunculated on the splenic vessels with 2 h of reperfusion in an untreated, an L-arginine- and a sodium-nitroprusside-treated group (Wistar rats, n = 7/group). Animals without ischemia served as controls. Tissue oxygenation (pO(2ti)) was monitored using a pO2-sensitive Clark-type electrode. Histological investigation was performed following a semiquantitative score (edema, vacuolization, PMN infiltration, necrosis). Plasma lipase was another marker of organ damage. RESULTS: The administration of L-arginine and sodium nitroprusside caused a significant amelioration of the decrease in pO2i) after reperfusion compared to IR animals (p < 0.05). Histological damage was also reduced in the NO donor groups (p < 0.05). After reperfusion, plasma lipase in the L-arginine-treated animals was significantly lower compared to IR and sodium nitroprusside (p < 0.05). CONCLUSIONS: The administration of both endogenous and exogenous NO donors is protective in IRI of the rat pancreas which can be seen by an improvement in post-ischemic tissue oxygenation which indicates better nutritive tissue perfusion, amelioration of the histological tissue injury and, in L-arginine animals, lower lipase levels. NO donors could be useful in the prevention and reduction of the pancreatic IRI.
Kupffer cells, ED2+macrophages of the liver, play an important role in liver damage and regeneration. It is proposed that Kupffer cells are stationary and regenerate after acute liver trauma by local proliferation. We analyzed their kinetics in three surgically relevant murine models of acute liver injury: partial liver resection, ischemia with reperfusion and sepsis. We found an early increase in ED2+cells after 0.5 h and a maximum after 12 h. These results suggest an infiltration of the cells early after the injury and a later local proliferation. These ED2+macrophages are localized predominantly periportally; nearly no macrophages are found pericentrally, except in the sepsis model. Therefore, a shifting of macrophages from portal to central seems to be unlikely, suggesting a hepatic zonation of homing factors.
A 20-year-old male patient with morbus Wilson was liver transplanted because of terminal failure of liver function. The explanted liver showed a strong macronodular cirrhosis as typically seen in Wilson disease. There were visible granular accumulations in the hepatocytes after the rubeanic acid or rhodanine method for histochemical detection of copper. The electron microscopic studies on ultrathin sections revealed numerous electron-dense lysosomes and residual bodies. The elemental analysis in transmission electron microscope (TEM) with electron energy loss spectroscopy (EELS) and in scanning electron microscope (SEM) with energy dispersive x-ray analysis (EDX) showed copper-specific signals of electron-dense accumulations inside these dark lysosomes and residual bodies. In a second case, Wilson disease was diagnosed after autopsy of a 31-year-old patient by liver electron microscopy and EELS; strong electron-dense lysosomes and residual bodies with positive copper signals were found inside hepatocytes. For negative control, hepatocytes with iron accumulation after idiopathic hemochromatosis and liver cirrhosis were also analyzed by EELS in TEM, which showed strong iron, but only a few or no copper signals. Atomic absorption spectroscopy (AAS) in 16 liver samples of healthy and cirrhotic liver revealed only in both cases of Wilson disease a strong increased copper concentration higher than 100 microg Cu/g. The electron microscopic detection of copper-containing hepatocytic lysosomes is helpful for the diagnosis of early stages of Wilson disease in addition to the quantification of hepatic copper by AAS.
BACKGROUND: Chemokines (CKs) may promote antitumor immunity in cancer, act as tumor growth factors, influence metastatic spreading or angiogenesis. The purpose of this study was to investigate whether CK expression is altered in colorectal carcinomas compared to normal mucosa and to elucidate its possible clinico-pathological implications. MATERIALS AND METHODS: The levels of CCL2 (MCP-1), CCL4 (MIP-1beta), CCL5 (RANTES), CXCL 1 (GRO-alpha), CXCL 5 (ENA-78) and CXCL 8 (IL-8) were investigated in 10 colorectal carcinomas and their corresponding normal mucosa by the use of ELISA. RESULTS: All CK analyzed, with the exception of CCL5 (RANTES), were expressed at a significantly higher level in malignant tissue. CONCLUSION: Therapeutic studies in colon carcinomas should, therefore, focus more on the neutralization of CKs than on their application.