BACKGROUNDWe investigated the role of 1,25-dihydroxyvitamin D3(1,25-(OH)2D3) in preventing allograft from acute rejection following orthotopic liver transplantation.

METHODSA rat orthotopic liver transplantation model was used in this study. SD-Wistar rats served as a high responder strain combination. Recipients were subjected to administration of 1,25-(OH)2D3 at dosages ranging from 0.25 microg.kg(-1).d(-1) to 2.5 microg.kg(-1).d(-1). Survival after transplantation as well as pathological rejection grades and IFN-gamma mRNA, IL-10 mRNA transcription intragraft on day 7, and day 30 post-transplantation were observed.

RESULTSAfter recipients were treated with 1,25(OH)2D3 at dosages of 0.5 microg.kg(-1).d(-1) or 1.0 microg.kg(-1).d(-1), survivals of recipients were prolonged. Ninety-five percent confidence intervals of survival were 46 - 87 days and 69 - 102 days (both P = 0.0005 vs control group), respectively. On day seven post-transplantation, relative levels of IFN-gamma mRNA transcription were 0.59 +/- 0.12 and 0.49 +/- 0.16, which was higher than the control group (P = 0.005, P = 0.003, respectively). Relative levels of IL-10 mRNA transcription were 0.83 +/- 0.09 and 0.76 +/- 0.09, which was lower than the control group (P = 0.002, P = 0.003, respectively). At a dosage of 0.5 microg.kg(-1).d(-1), the median of pathological rejection grade on day seven and on day thirty post-transplantation were 1.5 and 2.0 in comparison with the CsA-treated group (P = 0.178, P = 0.171, respectively). At a dosage of 0.5 microg.kg(-1).d(-1), the median of pathological rejection grade on day seven and day thirty post-transplantation were 1.5 and 1.5 in comparison with CsA-treated group (P = 0.350, P = 0.693, respectively).

CONCLUSIONAfter each recipient was treated with 1,25-(OH)2D3 at a dosage of (0.5 - 1.0) microg.kg(-1).d(-1), transcription of cytokine intragraft was accommodated effectively and deviated to Th2 type, resulting in alleviation of acute rejection. 1,25-(OH)2D3 can prolong survival of recipient after orthotopic liver transplantation.

Animals ; Calcitriol ; pharmacology ; physiology ; Graft Rejection ; prevention & control ; Interferon-gamma ; genetics ; Interleukin-10 ; genetics ; Liver Transplantation ; mortality ; Male ; Rats ; Rats, Sprague-Dawley ; Rats, Wistar ; Transcription, Genetic

OBJECTIVERetrospectively analyzing post-transplant primary biliary cirrhosis patients to document the actual survival time, the cause of post-transplant death, and recurrences after liver transplantation in patients followed up by the Queensland Liver Transplant Service (QLTS).

METHODSThe case notes of all post-piggyback liver transplantation patients followed up by QLTS were reviewed. We analyzed the clinical characteristics of the PBC patients, post-transplant actual survival rates, the causes of post-transplant death, and risk factors of recurrence, and compared the survival rates between patients with and without liver transplantation using a European model.

RESULTSFifty-two post-transplant patients with 54 transplantations were identified with an average age of 53 years and a mean follow-up time of 55 months. The actual survival times of PBC patients with grafts for 1 years, 5 years and 10 years were 88.4%, 80.1%, 76.9% and 80.9%, 65.4%, 19.8%. The causes of death were MOF intra-abdominal bleeding, renal failure, sepsis and cardiovascular diseases. Comparing the survival rates between with and without transplantation, 8.5% of PBC patients have recurrences with an average recurrent time of 34 months.

CONCLUSION(1) Liver transplantation could improve survival rates, but the optimum time for transplantation should be focused on; (2) A long-term and larger follow-up sampling should be done to understand the effects of recurrences on patient's long-term survival; (3) CsA may play a more important role in preventing recurrence of PBC than Tacrolimus

Cyclosporine ; therapeutic use ; Female ; Follow-Up Studies ; Graft Rejection ; prevention & control ; Humans ; Liver Cirrhosis, Biliary ; surgery ; Liver Transplantation ; mortality ; Male ; Middle Aged ; Postoperative Period ; Retrospective Studies ; Secondary Prevention ; Survival Rate ; Treatment Outcome

BACKGROUNDVitamin D3 and its metabolites have been found to exert immunosuppressive effects both in vivo and in vitro. We investigated the synergistic effect of calcitriol and cyclosporine A (CsA) on lymphocyte proliferation in vitro and graft rejection following rat liver allotransplantations in vivo.

METHODSAlloantigen driven, human peripheral mononuclear cells' proliferation and cytokine production capacity were tested in the presence or absence of various concentrations of calcitriol or CsA. In vivo, liver allografts were transplanted in a high responder strain combination (SD to Wistar) rats and combination of subtherapeutical dose of CsA and calcitriol was administered in recipients, whereas the control recipients received single or no immunosuppressant. Proliferation of splenocyte from recipient was tested with mixed lymphocyte reaction. Serum interleukin-2 (IL-2) and interferon gamma (IFN-gamma) concentrations were measured with enzyme linked immunosorbent assay.

RESULTSCombined medication of 10(-9) mol/L calcitriol and 100 ng/ml CsA inhibited human peripheral mononuclear cells' proliferation to alloantigen and the production of IL-2 and IFN-gamma but promoted that of IL-4 and IL-10. Similarly, combination of 250 ng x g(-1) x d(-1) calcitriol and 1.0 mg x g(-1) x d(-1) CsA showed an additive effect in liver transplant model. It restrained splenocyte proliferation to alloantigen from donor and significantly reduced serum concentration of IL-2 and IFN-gamma in recipients. Consequently, allograft rejection in combined medication group was minor (median William's grade was 1.0 vs 3.0 in combined medication group and in the control group, P < 0.05) and the recipients' survival was evidently prolonged [(93.7 +/- 5.8) days vs (12.6 +/- 1.4) days in combined medication group and in the control group, P < 0.01].

CONCLUSIONA combination of calcitriol and CsA has an additive effect on limiting lymphocyte proliferation and prolonging liver graft survival. With its additional immunomodulating property, calcitriol is a potent immunosuppressant that can extend the therapeutic window of classical immunomodulators in prevention and treatment of liver graft rejection.

Animals ; Calcitriol ; pharmacology ; Cells, Cultured ; Cyclosporine ; pharmacology ; Cytokines ; biosynthesis ; Drug Synergism ; Graft Rejection ; prevention & control ; Humans ; Liver Transplantation ; mortality ; Lymphocyte Activation ; drug effects ; NFATC Transcription Factors ; metabolism ; Rats ; Rats, Sprague-Dawley ; Rats, Wistar ; Transplantation, Homologous

BACKGROUNDPrevious studies using knockout mice document a key role for the integrin CD103 in promoting organ allograft rejection and graft-versus-host disease. However, a determination of whether blockade of the CD103 pathway represents a viable therapeutic strategy for intervention in these processes has proven problematic due to the lack of reagents that efficiently deplete CD103(+) cells from wild type hosts. To circumvent this problem, in the present study, we invented an anti-CD103 immunotoxin (M290-SAP). We investigated whether M290-SAP has capacity to eliminate CD103-expressing cells in vivo and protect transplanted islets from destroying by host immune cells.

METHODSFlow cytometry was used to analyze the efficacy of M290-SAP in depleting CD103-expressing cells in vivo. Then using allogenic islet transplantation models as well as NOD mice with recent onset type 1 diabetes, the therapeutic efficacy of CD103-expressing cell depletion was addressed.

RESULTSM290-SAP dramatically reduces the frequency and absolute numbers of CD103-expressing leukocytes in peripheral lymphatic tissues of treated mice. Balb/c islets transplanted into streptozotocin-induced diabetic C57BL/6 mice under single M290-SAP treatment showed an indefinite survival time compared with untreated mice, M290-treated mice and IgG-SAP treated mice (mean survival time, > 100 days vs. < 20 days). C57BL/6 islets transplanted into hyperglycemic NOD mice under single M290-SAP treatment showed a pronounced delay in allograft rejection compared with untreated mice (mean survival time 12 - 13 days vs. < 7 days). Immunological analysis of mice with long-term islet allograft survival revealed an obvious atrophy thymus and severe downregulation of alloimmunity of CD8 subpopulation response to allogenic stimulation.

CONCLUSIONRegardless of the underlying mechanisms, these data document that depletion of CD103-expressing cells represents a viable strategy for therapeutic intervention in islet allograft rejection.

Animals ; Antibodies, Monoclonal ; pharmacokinetics ; therapeutic use ; toxicity ; Antigens, CD ; analysis ; Female ; Graft Rejection ; prevention & control ; Graft Survival ; drug effects ; Integrin alpha Chains ; analysis ; antagonists & inhibitors ; Islets of Langerhans Transplantation ; immunology ; mortality ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Inbred NOD ; Thymocytes ; classification ; drug effects ; Transplantation, Homologous

BACKGROUND/AIMS: The relationship between patient survival and biopsy-proven acute rejection (BPAR) in liver transplant recipients with hepatitis C remains unclear. The aims of this study were to compare the characteristics of patients with and without BPAR and to identify risk factors for BPAR. METHODS: We retrospectively reviewed the records of 169 HCV-RNA-positive patients who underwent LT at three centers. RESULTS: BPAR occurred in 39 (23.1%) of the HCV-RNA-positive recipients after LT. The 1-, 3-, and 5-year survival rates were 92.1%, 90.3%, and 88.5%, respectively, in patients without BPAR, and 75.7%, 63.4%, and 58.9% in patients with BPAR (P<0.001). Multivariate analyses showed that BPAR was associated with the non-use of basiliximab and tacrolimus and the use of cyclosporin in LT recipients with HCV RNA-positive. CONCLUSION: The results of the present study suggest that the immunosuppression status of HCV-RNA-positive LT recipients should be carefully determined in order to prevent BPAR and to improve patient survival.
Antibodies, Monoclonal/therapeutic use ; Biopsy ; Cyclosporine/therapeutic use ; Drug Therapy, Combination ; Genotype ; Graft Rejection/mortality/*prevention & control ; Hepacivirus/genetics/isolation & purification ; Hepatitis C/drug therapy/*virology ; Humans ; Immunosuppressive Agents/*therapeutic use ; *Liver Transplantation/adverse effects ; Polymerase Chain Reaction ; RNA, Viral/blood ; Recombinant Fusion Proteins/therapeutic use ; Recurrence ; Retrospective Studies ; Survival Rate ; Tacrolimus/therapeutic use

During the past few years, new immunosuppressants, such as tacrolimus, mycophenolate mofetil (MMF) and basiliximab, have been shown to successfully decrease the incidence of acute rejection, possibly acting as potent substrates for safe steroid withdrawal. Therefore, clinical outcome of 3 months steroid withdrawal, while using the above immunosuppressants, was analyzed. Clinical trial registry No. was NCT 01550445. Thirty de novo renal transplant recipients were enrolled, and prednisolone was slowly withdrawn 3 months post-transplantation by 2.5 mg at every two weeks, until 8 weeks. During steroid withdrawal, 10 patients (30.0%) discontinued the protocol and they were maintained on steroid treatment. Among 20 steroid free patients, 8 patients (40.0%) re-started the steroid within 12 months post-transplantation. By the study endpoint, 12 (40%) recipients did not take steroid and survival of patients and grafts was 100%. In conclusion, in kidney transplant patients, 3 months steroid withdrawal while taking tacrolimus, basiliximab and mycophenolate mofetil was not associated with increased mortality or graft loss. Despite various causes of failure of steroid withdrawal during the follow-up period, it is a strategy well advised for kidney transplant recipients with regard to long-term steroid-related complications.
Adult ; Anti-Inflammatory Agents/*therapeutic use ; Antibodies, Monoclonal/therapeutic use ; Blood Urea Nitrogen ; Cholesterol/blood ; Creatinine/blood ; Female ; Graft Rejection/mortality/*prevention & control ; Humans ; Immunosuppressive Agents/*therapeutic use ; *Kidney Transplantation ; Male ; Middle Aged ; Mycophenolic Acid/analogs & derivatives/therapeutic use ; Prednisolone/*therapeutic use ; Prospective Studies ; Recombinant Fusion Proteins/therapeutic use ; Tacrolimus/therapeutic use

During the past few years, new immunosuppressants, such as tacrolimus, mycophenolate mofetil (MMF) and basiliximab, have been shown to successfully decrease the incidence of acute rejection, possibly acting as potent substrates for safe steroid withdrawal. Therefore, clinical outcome of 3 months steroid withdrawal, while using the above immunosuppressants, was analyzed. Clinical trial registry No. was NCT 01550445. Thirty de novo renal transplant recipients were enrolled, and prednisolone was slowly withdrawn 3 months post-transplantation by 2.5 mg at every two weeks, until 8 weeks. During steroid withdrawal, 10 patients (30.0%) discontinued the protocol and they were maintained on steroid treatment. Among 20 steroid free patients, 8 patients (40.0%) re-started the steroid within 12 months post-transplantation. By the study endpoint, 12 (40%) recipients did not take steroid and survival of patients and grafts was 100%. In conclusion, in kidney transplant patients, 3 months steroid withdrawal while taking tacrolimus, basiliximab and mycophenolate mofetil was not associated with increased mortality or graft loss. Despite various causes of failure of steroid withdrawal during the follow-up period, it is a strategy well advised for kidney transplant recipients with regard to long-term steroid-related complications.
Adult ; Anti-Inflammatory Agents/*therapeutic use ; Antibodies, Monoclonal/therapeutic use ; Blood Urea Nitrogen ; Cholesterol/blood ; Creatinine/blood ; Female ; Graft Rejection/mortality/*prevention & control ; Humans ; Immunosuppressive Agents/*therapeutic use ; *Kidney Transplantation ; Male ; Middle Aged ; Mycophenolic Acid/analogs & derivatives/therapeutic use ; Prednisolone/*therapeutic use ; Prospective Studies ; Recombinant Fusion Proteins/therapeutic use ; Tacrolimus/therapeutic use