The pathogenesis of fibrosis in chronic renal allograft rejection remains unknown. Since TGF-beta 1 plays a key role in fibrogenesis, we studied a rat model of chronic allograft rejection that shows similarities to the structural lesion described in patients. We previously demonstrated an increased expression of TGF-beta 1 in human kidney biopsies with acute and chronic rejection. Recipients of renal allografts (F344-Lewis) and isografts (Lewis-Lewis) were sacrificed at 4, 8, 24 and 52 weeks. Characteristic histologic changes of chronic rejection developed in the allografts as early as four weeks and were accompanied by progressive albuminuria significant by eight weeks. Allografts showed a progressive increase in mRNA expression of TGF-beta 1 and matrix proteins during the 52 week course. Increased matrix deposition by immunofluorescence was mostly present in the interstitium and vessels early and in all kidney compartments later. The mRNA expression of plasminogen activator inhibitor, a protease inhibitor stimulated by TGF-beta 1, increased along with TGF-beta 1 and matrix proteins. These results suggest that the fibrosis of chronic renal allograft rejection is mediated, at least partly, by the dual action of TGF-beta 1 on matrix deposition and degradation.
Clinical studies have revealed a correlation between cytomegalovirus (CMV) infection and acute allograft rejection. Likewise, for a murine model we observed that C3H (H-2k) recipients infected with murine CMV (MCMV) rejected BALB/c (H-2") cardiac allografts earlier than uninfected recipients (6.9±0.1 d compared with 8.1±0.6 d; P < 0.001). It has been hypothesized that MCMV epitopes crossreact with alloantigens and in this manner induce rejection. However, we also demonstrated that MCMV caused accelerated rejection in the reverse combination (C3H heart engrafted to BALB/c recipient; 7.2±0.3 and 9.4±0.4 d for infected and control animals, respectively; P < 0.001 ) and accelerated rejection of grafts of a third, unrelated haplotype (C57BI/6; H-2b; 8.0±0.7 d compared with 10.1±0.6 for infected and control C3H recipients, respectively; P < 0.03). Ultraviolet (UV) inactivation of MCMV before administration to the graft recipient abrogated the ability to induce rapid rejection. Activated T lymphocytes were present in grafts from infected recipients 2 d before control recipients (P < 0.02) and, at the time of graft rejection, were almost exclusively CD8+ for both infected and control recipients. Thus, MCMV accelerated rejection appears not to result from crossreaction between MCMV epitopes and MHC products. The failure of UV-inactivated virus to accelerate rejection and the high proportion of CD8+ T cells recovered from all rejected grafts suggest that the class I pathway of antigen presentation may be important in the induction of early rejection. (J. Clin. Invest. 1993.91:2602-2608
Interleukin-18 (IL-18) and IL-12 have been shown to play an important role in the induction of interferon-gamma (IFN-gamma). IFN-gamma induces the proliferation of T cells and natural killer (NK) cells and augments the Th1 immune cascade. The role of IL-18 and IL-12 in the induction of IFN-gamma following allogeneic heart transplantation has not been described. We sought to characterize the IL-12 and IL-18 response to murine allogeneic heart transplantation, particularly with respect to IFN-gamma production and histologic transplant rejection. Forty-eight heterotopic heart transplants were performed in two groups of mice: syngeneic C3H/HeN to C3H/HeN mice and allogeneic BALB/C to C3H/HeN mice. Transplants were followed out to 2, 6, 10, and 14 days. Six transplants were performed in each group. Serum and splenic samples were used to evaluate the cytokine response by ELISA. Explanted heart tissue was processed for evidence of histologic rejection, and RT-PCR was performed to evaluate the IL-12, IL-18, and IFN-gamma signal qualitatively. Analysis of variance (ANOVA), Fisher's projected least significant difference (PLSD) was used for statistical analysis. Transplant rejection occurred in the allogeneic group histologically by day 6 and clinically by day 10. Serum IFN-gamma levels rose significantly by day 6 in the allogeneic group and then continued to rise in the splenocyte cultures. Serum IL-18 also rose significantly in the allogeneic group at day 6 compared with syngeneic group. RT-PCR revealed that the allogeneic tissue contained an increased signal for IL-12, IL-18, and IFN-gamma beginning at day 6 and peaking at day 10 after transplant. Beginning 6 days after transplantation, IL-12 and IL-18 appear to play a significant role in the induction of IFN-gamma in allogeneic heart transplants.
Background: Gastric ileus is an unsolved clinical problem and current treatment is limited to supportive measures. Models of ileus using anesthetized animals, muscle strips or isolated smooth muscle cells do not adequately reproduce the clinical situation. Thus, previous studies using these techniques have not led to a clear understanding of the pathophysiology of ileus. The feasibility of using food intake and fecal output as simple, clinically relevant endpoints for monitoring ileus in a conscious mouse model was evaluated by assessing the severity and time course of various insults known to cause ileus.
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