摘要:

Background.Costimulation blockade has been proposed to induce allograft tolerance. We combined an antagonist anti-CD40 monoclonal antibody (mAb) with an antagonist anti-CD86 mAb in a rhesus monkey kidney allograft model. We chose this combination because it leaves CD80-CD152 signaling unimpaired, allowing for the down-regulatory effect of CD152 signaling to take place through this pathway.Methods.Rhesus monkeys underwent transplantation with a major histocompatibility complex–mismatched kidney. One group of animals received anti-CD40 alone, and a second group received the combination of anti-CD40 and anti-CD86, twice weekly for 56 days.Results.Three animals with low levels of anti-CD40 rejected the transplanted kidney while still receiving treatment. Three animals with high levels of anti-CD40 rejected at days 91, 134, and 217 with signs of chronic rejection. Animals treated with the combination of anti-CD40 and anti-CD86 mAbs rejected their kidneys at days 61, 75, and 78, shortly after cessation of treatment. Two animals were killed on days 71 and 116 with a blocked ureter. These animals developed virtually no signs of tubulitis or infiltration during treatment and no donor-specific alloantibodies.Conclusions.Both treatment protocols prevented rejection for the duration of the treatment in most animals. Blocking costimulation by anti-CD40 or by anti-CD40 plus anti-CD86 may be an effective method to prevent graft rejection and may obviate the need for other immunosuppressive drugs, especially in the immediate posttransplantation period.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.Costimulation blockade has been shown to be effective in achieving donor-specific immune unresponsiveness in models of organ transplantation. This study represents the first application of blockade of the CD40 costimulatory pathway to a murine model of limb allotransplantation.Methods.Eighteen Balb/c mice (H-2Kd) were randomized to four groups. The control group (n=5) received syngeneic limb transplants from Balb/c donors. The experimental groups were recipients of limb allografts from C57Bl/6 mice (H-2Kb) and received either no treatment (n=5) or treatment with MR1 (hamster antimouse CD40 ligand monoclonal antibody) 500 &mgr;g intraperitoneally (IP) on days 0, 2, 4, 6, 14, 28, and 60 (n=5). A fourth group received myocutaneous allografts from C57Bl/6 donors and the same treatment with MR1 (n=5).Results.Untreated limb allografts were rejected at a mean of 9.6±1.1 days postoperatively. MR1-treated limb allografts underwent rejection of the skin component at a mean of 75±25 days whereas the musculoskeletal component survived to a mean of 222±84 days with two allografts surviving more than 10 months (P<0.001). The MR1-treated myocutaneous allografts were rejected after 16.2±2 days. All groups demonstrated acute rejection on histology except the treated limb allograft group, which was more suggestive of a chronic process. No chimerism was detected in this group by flow cytometry.Conclusions.CD40 costimulatory blockade significantly prolonged limb-allograft survival, and the bone-marrow component may have played an important role. Tolerance was not achieved, and histologic evaluation suggested chronic rejection as a possible cause of allograft loss.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.Although recurrent lupus nephritis (RLN) after kidney transplantation is reported to be rare (1%–4%), recent studies suggest a higher incidence. The purpose of this study was to determine the incidence of RLN in a large cohort of renal transplant recipients with systemic lupus erythematosus (SLE).Methods.The records of 54 renal transplant recipients with SLE were reviewed. Thirty-one patients underwent biopsy because of worsening renal function and proteinuria. All biopsy specimens were evaluated by light microscopy, immunofluorescence (IF), and electron microscopy (EM).Results.Among the 50 patients with at least 3 months of follow-up, RLN was present in 15 (52% of patients who underwent biopsy, 30% of total patients): mesangial lupus nephritis (LN) (class II) in eight, focal proliferative LN (class III) in four, and membranous LN (class Vb) in three patients. One patient had graft loss because of RLN (class II) at 10.5 years. The duration of dialysis before transplantation was not different between patients with RLN compared to patients without RLN (P=0.40). Overall patient survival (n=50) was 96% at 1 year and 82% at 5 years, and graft survival was 87% at 1 year and 60% at 5 years. Graft survival was worse in patients who underwent biopsy compared with patients who never underwent biopsy (P<0.01).Conclusions.RLN is more common than previously reported, but in our series, graft loss because of RLN was rare. Aggressive use of allograft biopsies and morphologic evaluation with IF and EM are important factors in the diagnosis of RLN. The impact of new immunosuppressive agents on the incidence of RLN remains to be seen.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.Polyclonal antithymocyte globulins (ATG) induce T-cell depletion and functional impairment of nondeleted lymphocytes. Interference of ATG with the main leukocyte surface molecules involved in cellular adhesion and leukocyte-endothelium interaction was investigated in the present study.Methods.In three rabbit ATG, the authors measured antibodies to integrins, &bgr;2-integrin ligands, and chemokine receptors by flow cytometry; chemotactic responses; and down-modulation of cell surface expression on lymphocytes, monocytes, and neutrophils.Results.Antibodies to CD11a/CD18 (leukocyte function-associated antigen-1 [LFA-1]) present in ATG induced a dose-dependent down-modulation of cell surface expression of this &bgr;2 integrin on lymphocytes, monocytes, and neutrophils. In contrast, anti–LFA-1 monoclonal antibodies did not induce LFA-1 modulation unless cross-linked by a second antibody. ATG also contained functional antibodies to the &bgr;1 integrin CD49d/CD29 (VLA-4), the &agr;4&bgr;7 integrin, CD50, CD54, and CD102 but not to CD62L. ATG were shown to bind to CXCR4 and CCR7 on lymphocytes, CXCR4, and CCR5 on monocytes; to down-modulate cell surface expression of CCR7; and to decrease monocyte chemotactic response to CCL5 (RANTES) and lymphocyte chemotactic response to CCL19 (MIP-3&bgr;).Conclusion.These results show that ATG may interfere with leukocyte responses to chemotactic signals but mostly inhibit the expression of integrins required for firm cellular adhesion. The latter property of inhibition is not shared by monoclonal antibodies, and it may contribute to decreasing graft cellular infiltration during acute rejection and possibly after postischemic reperfusion.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.Acute humoral rejection (AHR) is the most important risk factor for early graft loss in ABO-incompatible (ABO-i) kidney transplantation (RTx). The pathogenesis and diagnostic criteria for AHR after ABO-i RTx remain unclear. Complement fragment C4d deposition in peritubular capillaries (PTC), which is a sensitive indicator for activation of the classical complement pathway, was studied to establish the pathologic diagnostic indicator of AHR.Methods.Forty-four graft biopsy specimens from 19 patients with ABO-i living donors were analyzed within 90 days after RTx. Nineteen biopsy specimens with acute rejection after ABO-compatible (ABO-c) living-related RTx were used as controls. Diffuse and bright C4d deposition in PTC was considered significantly positive.Results.All of 8 recipients with AHR showed significantly positive C4d in PTC in the ABO-i group, but 9 of 11 recipients without AHR were negative. In the ABO-c RTx group, 16 of 19 recipients were negative for C4d in PTC. The prevalence of C4d in PTC was significantly higher in ABO-i RTx (P<0.05).Conclusions.C4d deposition is valuable as a specific and sensitive indicator for AHR, even of mild severity, in ABO-i RTx.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.Diarrhea is the most frequently reported adverse event in mycophenolate mofetil (MMF)-treated transplant patients. The aim of this study was to explore the gastrointestinal tract in MMF-treated renal transplant recipients with persistent afebrile diarrhea to characterize its nature and etiology.Methods.Renal transplant recipients with persistent afebrile diarrhea (daily fecal output >200 g) were prospectively investigated for infections, morphologic, and functional (gastrointestinal motility and intestinal absorptive capacity) integrity of the gastrointestinal tract; 26 patients met the inclusion criteria.Results.All but one patient had an erosive enterocolitis. Seventy percent of the patients had malabsorption of nutrients, contributing to the diarrhea. In ±60%, an infectious origin was demonstrated and successfully treated with antimicrobial agents without changes in immunosuppressive regimen. In ±40%, no infection occurred, but a Crohn’s disease-like pattern of inflammation was noted. These patients also had a less pronounced bile-acid malabsorption but a significant faster colonic transit time, correlating with the trough level of mycophenolic acid (MPA). Cessation of MMF, however, was associated with allograft rejection in one third of these patients.Conclusions.Persistent afebrile diarrhea in renal transplant recipients is characterized by erosive enterocolitis, which is of infectious origin in ±60%. In ±40%, a Crohn’s disease-like (entero-)colitis was present. Because reduction or cessation of MMF was the only effective therapy, MPA or one of its metabolites may be suggested as a possible cause. However, reduction or cessation of MMF was associated with an increased risk for rejection.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.The molecular mechanism of small-for-size graft injury remains unclear. The aim of this study is to investigate the gene expression pattern of acute phase response in relation to graft size in a rat-liver transplantation model.Methods.A rat orthotopic liver transplantation model using 30%, 50%, and whole grafts was used. The graft survival rates and liver morphology were compared among the three groups. Two transcription factors, nuclear factor (NF)-&kgr;B (p65) and early growth response (Egr-1), and their downstream genes were compared.Results.According to the graft size, the rats were grouped as follows: group 1 (n=20), 32% (24–47%); group 2 (n=10), 56% (50–65%); and group 3 (n=10), 104% (89–120%). The 7-day survival rates were 20% (P=0.039 vs. group 2,P=0.000 vs. group 3), 60%, and 100% in groups 1, 2, and 3, respectively. Dilation of hepatic sinusoids and vacuolization of hepatocytes were observed in group 1. Up-regulation of Egr-1 and endothelin (ET)-1 and over-expression of nitric oxide synthase (iNOS) was found in group 1, but heme oxygenase (HO)-1 and A20 were down-regulated. At 24 hours after reperfusion, the intragraft protein level of heat-shock protein (Hsp)-70 was significantly lower in group 1 than that in group 3 (12.4 vs. 17.0 ng/mL,P=0.04). More apoptotic nuclei were found in group 1.Conclusions.Small-for-size graft injury was related to early over-expression of Egr-1 associated with up-regulation of ET-1 and deterioration of intracellular homeostasis reflected by down-regulation of Hsps and A20.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.Mesenchymal stem cells (MSC) are pluripotent progenitors for a variety of cell types, including fibroblasts and muscle cells. Their involvement in the tissue repair of allografts during the development of chronic rejection has been hypothesized, but not yet substantiated, by experimental evidence.Methods.Rat MSC were isolated from circulation using an aortic pouch allograft as a trapping device. The plasticity of these cells was examined in differentiation cultures. One of the resulting MSC lines was immortalized and transduced to express a markerlaczgene. Thelacz-labeled cells were then transferred to F344 rats bearing Lewis (LEW) cardiac allografts to measure their localization and contribution to graft tissue repair.Results.The MSC isolated from circulation exhibited multipotential for differentiation in culture, developing into various lineages including osteoblasts, lipocytes, chondrocytes, myotubes, and fibroblasts. Intravenous engraftment of thelacz-labeled cells into recipients of heart transplant resulted in migration of the &bgr;-gal+ cells into the lesions of chronic rejection in the cardiac grafts and homing of the cells to the bone marrow. The majority of &bgr;-gal+ cells present in the allografts exhibited fibroblast phenotypes, and a small number of the cells expressed desmin, indicative of myocyte differentiation.Conclusion.MSC vigorously migrated into the site of allograft rejection. This data suggests that they may be attracted to this site to actively participate in tissue repair during chronic rejection. In addition, given the robust migration, the inhibition of MSC differentiation toward fibroblast progeny and induction toward the myocyte lineage may serve as a new strategy for treatment of chronic rejection and allograft tissue repair.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

During acute rejection of rat renal allografts, numerous activated monocytes accumulate in the vasculature of the graft. These monocytes seem to be involved in allograft destruction. Proinflammatory and effector functions of monocytes and macrophages can be down-regulated by peroxisome proliferators, which are probably transported in the cytoplasm by fatty acid binding proteins (FABPs). We performed renal transplantation in rats in the Dark Agouti-to-Lewis strain combination. Intravascular graft leukocytes were harvested 4 days posttransplantation. Epidermal (E)-FABP mRNA and protein expression were investigated by reverse-transcriptase polymerase chain reaction and immunoblotting, respectively. E-FABP-expressing cells were identified by immunofluorescence. After allogeneic transplantation, intravascular graft leukocytes expressed E-FABP mRNA and protein. In isografts, significantly lower expression levels were observed. E-FABP protein was detected in monocytes expressing ED1 and in &agr;&bgr;-T-cell receptor positive T lymphocytes. E-FABP might regulate monocyte activation and may represent a promising target for a therapeutic intervention in allograft rejection.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.The function of large arteries is altered after renal transplantation. Whether transplantation also induces agonist-dependent functional changes in small arterial renal and extrarenal vessels has not yet been studied.Methods.Chronic rejection was induced by grafting Lewis rats with kidneys from Fischer rats (FL). Rats that underwent transplantation were bilaterally nephrectomized. Rats that underwent syngeneic transplantation, uninephrectomized rats, uninephrectomized rats with denervated kidneys or with kidneys made ischemic, and native rats served as controls. All animals were treated with cyclosporine for 10 days. Eighteen weeks after surgery, the reactivity of small arteries (220–270 &mgr;m) was tested by myography.Results.Weight gain, glomerular filtration rate, and arterial pressure were similar in all groups, whereas proteinuria was elevated in FL. Only kidneys from FL showed glomerular lesions, tubular atrophy, and vasculopathy. Responsiveness of coronary, mesenteric, and femoral resistance vessels to both constrictor and dilator agonists was similar in transplanted and nontransplanted animals. Resistance vessels obtained from both allogeneically and syngeneically transplanted kidneys were more sensitive to norepinephrine, phenylephrine, angiotensin II, and vasopressin than renal vessels from weight-matched controls. Vasodilation in response to acetylcholine and sodium nitroprusside was mitigated in transplanted versus nontransplanted kidneys.Conclusions.In rat renal transplantation, renal resistance vessel responsiveness to constrictor or dilator stimuli is altered. Extrarenal small vessel function is not affected. The changes in function of renal resistance vessels are not explained by reduction of nephron mass, denervation, ischemia, or chronic rejection.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID