- Email: [email protected]
Significance of immune activation in recipients with autoimmune-mediated liver diseases in liver transplantation
154A
AASLD ABSTRACTS
189 SIGNIFICANCE OF IMMUNE ACTIVATION IN RECIPIENTS WITH AUTOIMMUNE-MEDIATED LIVER DISEASES IN LIVER TRANSPLANTATION. M Havashi. SM Krams. OM Martinez. SKS So, and CO Esouivel. Transplantation Immunohiology Laboratory, California I3acific Medical Center, San Francisco, CA. The purpose of this study was to determine the impact of primary immune abnormalities on transplantation outcome in terms of allograft rejection and infection. M e t h o d s : 70 patients u n d e r g o i n g liver transplantation between 3/88 and 12/94 for end-stage liver disease due to autoimmune hepatitis (n=33), primary biliary cirrhosis (n=26), and primary sclerosing cholangitis (n=11) were compared with 51 patients transplanted for alcoholic liver disease in the same period. Patients with concomitant hepatitis B or C were excluded. Results; The age, UNOS status, standard immunosuppression, observation period (>6 months), and histological grade of rejection were not statistically different between the two groups. There was a significantly reduced incidence of rejection after induction with tacrolimus compared to cyclosporin-based immunosuppression. However, patients with autoimmune liver disease had a significantly higher incidence of rejection as compared to alcoholic liver disease irregardless of immunosuppressive drugs. There was no evidence of autoimmune disease recurrence. Autoimmune liver disease Alcoholic liver disease Acute r~ection (AR) NumberofAR n--0 episodes: n=l n-22 Frequency of ARt-
83°/0* 17% * 56% 27%* 1.18±0.7 *
51% 49% 49% 2% 0.58+0.55
Steroid-resistent Chronic reiection CMV disease Mortality rate
38% 31% 11% * 2% 13% 6% 11.1% 11.8% ('i': mean+SD; * : p<0.05 between two groups) Conclusions: Primary immune activation leads to an increased incidence of both acute and chronic rejection following liver transplantation.
191
DONOR ORGAN COLD ISCHEMIA TIME AND OUTCOME FOLLOWING LIVER TRANSPLANTATION. S Belle* and RK Zetterman, for the NIDDK Liver Transplantation Database. *University of Pittsburgh and University o f Nebraska Medical Center Extended cold ischemia time (CIT) has been suggested to increase biliary complications and other adverse events following orthotopic liver transplantation (OLT}. The aim of this study was to examine the relationship between CIT and clinical and histologic outcomes following OLT in 3 transplant centers. METHODS: The NIDDK Liver Transplantation Database (LTD) enrolled 916 OLT recipients from 3 participating centers (Mayo Clinic, University of Nebraska Medical Center, University of California San Francisco) from 4/90 through 6/94. For this study, data from 705 patients were used, excluding fulminant hepatic failure (58), children (94), recipients of a multi-organ transplantation (26), recipients of a liver not preserved with UW solution (15), and those with unknown CIT (18). CIT was examined in hours (as a continuous variable), and also categorized as < 12 vs -> 12 hours (hrs) and < 15 vs >- 15 hrs. RESULTS: The median cold ischemia time was 9.8 hrs; 29.8% had _>12 hrs CIT and 13.0% had ->15 hrs CIT. Recipients of organs with either -> 12 hrs or -> 15 hrs CIT required longer hospitalizations (p<.01) and ICU stays (p<.O01). The odds of allograft dysfunction within 10 days rose by 9 % for every hour of increased CIT (p< .001 ). Four weeks after OLT, neither patient (p > .20) nor graft (p>.09) survival differed significantly. However, acute rejection within 4 weeks was significantly more common among those with ->15 hrs CIT (59.3% vs 3 9 , 9 % < 1 5 hrs, p < . 0 1 ) . By one year following OLT, no excess complications due to biliary tract injury (p>.9) or intrahepatic strictures (p>.5) were reported. CONCLUSION: Longer CIT is associated with more early allograft dysfunction and results in longer hospital and ICU stays but does not result in more biliary tract injury.
HEPATOLOGYOctober 1995
190 PRECIPITATION OF FATAL REJECTION OF SPONTANEOUSLY ACCEPTED MHC MISMATCHED RAT LIVER ALLOGRAFTS BY ADMINISTRATION OF EXOGENOUS INTERLEUKIN 2 (IL-2). Yizheng Tu, Atiq Rehman, Takeshi Arima. and M. Wayne Flye. Dept. of Surgery, Washington University, St. Louis, Missouri. T cell activation requires at least two signals including perturbation of the antigen specific T cell receptor (TCR) plus a costimulatory signal. Absence of the second signal in stimulation of T lymphocytes has been shown to result in anergy and graft tolerance. MHC incompatible Lewis (RT1]; LEW) to D Agonti-RT1 = (DA) rat liver aIlografts are spontaneously accepted despite early infiltration by recipient mononucieated ceils that respond to IL-2 and exhibit donor-specific cytotoxieity that are indistinguishablefrom that observed in the reciprocal rejecting DA to LEW combination. The mechanism of this spontaneous liver graft acceptance is not known. Methods: Since anergy has been reversed in neonatally induced tolerance and in tolerant cardiac aUografts following donoi" specific blood transfusion, 180,000 units of human IL-2 was administered IP daily for 10 days, beginning on the day of Lew to DA orthotopic liver transplantation. Data were analyzed using the Mann-Whitney U test. Survival Bilirubin Bilirubin MST Treatment (days) day 7 day 11 (days) p value DA--*LEW 10,11,11,12, 11.5 12,13 LEWoDA 187,229,302, 270.8 310,326 LEW~DA IL-2 7,11,11,13 2.65+_0.3 7.1+3.4 10.5 0.0143 Results: The spontaneous acceptance of liver grafts was blocked with exogenous IL-2 in all 4 LEW~DA recipients, with a progressive increase in blood bilirubin during the development of fatal rejection, which was confirmed by histology that showed increasing cellular infiltration of the portal tracts, bridging necrosis and endothelialitis. Conclusion: Fatal rejection of spontaneously accepted rat liver grafts can be caused by the administration of exogenous IL-2, thus suggesting a deficiency in the generation of the critical Thl cytokine, IL-2, in this strain combination.
192 Microcirculatory Impairment During Acute Rejection: A Critical Component of Liver Graft Failure. J. X. Zhang, D. Wang, I. Bauer, M.G. Clemens, and A. Klein. The Johns Hopkins University School of Medicine, Baltimore, MD 21287. Despite advances in elinicai immunosuppresaion, acute rejection after liver transplantation (LT) remains a major obstacle to prolonged allograft survival. However, alterationswhich occur at the level of the hepatic microeirculation during the rejection process remain unclear. In the present study, we investigated the mieroeirculatory changes associated with early phase acute rejection of hepatic allografls. Four experimentalgroups were defined as: 1)acutely rejecting allogeneic LT (nile = August donor/Lewis recipient), 2) syngeneic LT (syn = Lewis donor/Lewis recipient), 3)Lewis sham control (Lew), and 4)August sham control (Aug). Three days after transplant, in viva videomicroscopy was performed to assess the changes in micrecirculation of the liver. The number of perfused sinasoids (PS), sinusoid diameter (Ds), and RBC velocity (V~c) were measured, and the perfusion index (PI) was calculated. As seen in the table below, PS in alia rats was markedlyreduced compared to syn rats and sham controls. No significant change was observed in the syn group compared to sham control. Ds in alia rats was increased, coincident with massive upregulation of iNOS as detected by Northern blot but the Vmc decreased significantly. The perfusion index in the alia group decreased by 56% whereas no change was seen in the syn group. Data are expressed as Mean±SE (P<0.05: * = alia vs syn; & = alia vs Aug).
Aug Lew syn alia
~ (#/mm) 40.51±1.31 35.83±0.67 32.215:1.87 20A2~2.04*&
D~ (~m) Vo.~ (urn~see) 10.475:0.12 386.13±9.09 10.115:0.18 421.035:13.18 10.575:0.16 460.115:14.28 11.385:0.28" 241.975:13.30"&
Pl(pl/sec.mm ~) 1345.005:57.29 1285.115:143.05 1335.555:84.56 594.505:99.31"&
In conclusion, profound alterations of the hepatic microcirculation, characterized by overt injury and impaired sinusoidal perfusion occur early during ~nte allograt~ rejection. We would suggest that this microcirculatory dysfunction may ultimately lead to graft failure. Supported by NU-Igrants DK02126 and DK38201.
AASLD ABSTRACTS
189 SIGNIFICANCE OF IMMUNE ACTIVATION IN RECIPIENTS WITH AUTOIMMUNE-MEDIATED LIVER DISEASES IN LIVER TRANSPLANTATION. M Havashi. SM Krams. OM Martinez. SKS So, and CO Esouivel. Transplantation Immunohiology Laboratory, California I3acific Medical Center, San Francisco, CA. The purpose of this study was to determine the impact of primary immune abnormalities on transplantation outcome in terms of allograft rejection and infection. M e t h o d s : 70 patients u n d e r g o i n g liver transplantation between 3/88 and 12/94 for end-stage liver disease due to autoimmune hepatitis (n=33), primary biliary cirrhosis (n=26), and primary sclerosing cholangitis (n=11) were compared with 51 patients transplanted for alcoholic liver disease in the same period. Patients with concomitant hepatitis B or C were excluded. Results; The age, UNOS status, standard immunosuppression, observation period (>6 months), and histological grade of rejection were not statistically different between the two groups. There was a significantly reduced incidence of rejection after induction with tacrolimus compared to cyclosporin-based immunosuppression. However, patients with autoimmune liver disease had a significantly higher incidence of rejection as compared to alcoholic liver disease irregardless of immunosuppressive drugs. There was no evidence of autoimmune disease recurrence. Autoimmune liver disease Alcoholic liver disease Acute r~ection (AR) NumberofAR n--0 episodes: n=l n-22 Frequency of ARt-
83°/0* 17% * 56% 27%* 1.18±0.7 *
51% 49% 49% 2% 0.58+0.55
Steroid-resistent Chronic reiection CMV disease Mortality rate
38% 31% 11% * 2% 13% 6% 11.1% 11.8% ('i': mean+SD; * : p<0.05 between two groups) Conclusions: Primary immune activation leads to an increased incidence of both acute and chronic rejection following liver transplantation.
191
DONOR ORGAN COLD ISCHEMIA TIME AND OUTCOME FOLLOWING LIVER TRANSPLANTATION. S Belle* and RK Zetterman, for the NIDDK Liver Transplantation Database. *University of Pittsburgh and University o f Nebraska Medical Center Extended cold ischemia time (CIT) has been suggested to increase biliary complications and other adverse events following orthotopic liver transplantation (OLT}. The aim of this study was to examine the relationship between CIT and clinical and histologic outcomes following OLT in 3 transplant centers. METHODS: The NIDDK Liver Transplantation Database (LTD) enrolled 916 OLT recipients from 3 participating centers (Mayo Clinic, University of Nebraska Medical Center, University of California San Francisco) from 4/90 through 6/94. For this study, data from 705 patients were used, excluding fulminant hepatic failure (58), children (94), recipients of a multi-organ transplantation (26), recipients of a liver not preserved with UW solution (15), and those with unknown CIT (18). CIT was examined in hours (as a continuous variable), and also categorized as < 12 vs -> 12 hours (hrs) and < 15 vs >- 15 hrs. RESULTS: The median cold ischemia time was 9.8 hrs; 29.8% had _>12 hrs CIT and 13.0% had ->15 hrs CIT. Recipients of organs with either -> 12 hrs or -> 15 hrs CIT required longer hospitalizations (p<.01) and ICU stays (p<.O01). The odds of allograft dysfunction within 10 days rose by 9 % for every hour of increased CIT (p< .001 ). Four weeks after OLT, neither patient (p > .20) nor graft (p>.09) survival differed significantly. However, acute rejection within 4 weeks was significantly more common among those with ->15 hrs CIT (59.3% vs 3 9 , 9 % < 1 5 hrs, p < . 0 1 ) . By one year following OLT, no excess complications due to biliary tract injury (p>.9) or intrahepatic strictures (p>.5) were reported. CONCLUSION: Longer CIT is associated with more early allograft dysfunction and results in longer hospital and ICU stays but does not result in more biliary tract injury.
HEPATOLOGYOctober 1995
190 PRECIPITATION OF FATAL REJECTION OF SPONTANEOUSLY ACCEPTED MHC MISMATCHED RAT LIVER ALLOGRAFTS BY ADMINISTRATION OF EXOGENOUS INTERLEUKIN 2 (IL-2). Yizheng Tu, Atiq Rehman, Takeshi Arima. and M. Wayne Flye. Dept. of Surgery, Washington University, St. Louis, Missouri. T cell activation requires at least two signals including perturbation of the antigen specific T cell receptor (TCR) plus a costimulatory signal. Absence of the second signal in stimulation of T lymphocytes has been shown to result in anergy and graft tolerance. MHC incompatible Lewis (RT1]; LEW) to D Agonti-RT1 = (DA) rat liver aIlografts are spontaneously accepted despite early infiltration by recipient mononucieated ceils that respond to IL-2 and exhibit donor-specific cytotoxieity that are indistinguishablefrom that observed in the reciprocal rejecting DA to LEW combination. The mechanism of this spontaneous liver graft acceptance is not known. Methods: Since anergy has been reversed in neonatally induced tolerance and in tolerant cardiac aUografts following donoi" specific blood transfusion, 180,000 units of human IL-2 was administered IP daily for 10 days, beginning on the day of Lew to DA orthotopic liver transplantation. Data were analyzed using the Mann-Whitney U test. Survival Bilirubin Bilirubin MST Treatment (days) day 7 day 11 (days) p value DA--*LEW 10,11,11,12, 11.5 12,13 LEWoDA 187,229,302, 270.8 310,326 LEW~DA IL-2 7,11,11,13 2.65+_0.3 7.1+3.4 10.5 0.0143 Results: The spontaneous acceptance of liver grafts was blocked with exogenous IL-2 in all 4 LEW~DA recipients, with a progressive increase in blood bilirubin during the development of fatal rejection, which was confirmed by histology that showed increasing cellular infiltration of the portal tracts, bridging necrosis and endothelialitis. Conclusion: Fatal rejection of spontaneously accepted rat liver grafts can be caused by the administration of exogenous IL-2, thus suggesting a deficiency in the generation of the critical Thl cytokine, IL-2, in this strain combination.
192 Microcirculatory Impairment During Acute Rejection: A Critical Component of Liver Graft Failure. J. X. Zhang, D. Wang, I. Bauer, M.G. Clemens, and A. Klein. The Johns Hopkins University School of Medicine, Baltimore, MD 21287. Despite advances in elinicai immunosuppresaion, acute rejection after liver transplantation (LT) remains a major obstacle to prolonged allograft survival. However, alterationswhich occur at the level of the hepatic microeirculation during the rejection process remain unclear. In the present study, we investigated the mieroeirculatory changes associated with early phase acute rejection of hepatic allografls. Four experimentalgroups were defined as: 1)acutely rejecting allogeneic LT (nile = August donor/Lewis recipient), 2) syngeneic LT (syn = Lewis donor/Lewis recipient), 3)Lewis sham control (Lew), and 4)August sham control (Aug). Three days after transplant, in viva videomicroscopy was performed to assess the changes in micrecirculation of the liver. The number of perfused sinasoids (PS), sinusoid diameter (Ds), and RBC velocity (V~c) were measured, and the perfusion index (PI) was calculated. As seen in the table below, PS in alia rats was markedlyreduced compared to syn rats and sham controls. No significant change was observed in the syn group compared to sham control. Ds in alia rats was increased, coincident with massive upregulation of iNOS as detected by Northern blot but the Vmc decreased significantly. The perfusion index in the alia group decreased by 56% whereas no change was seen in the syn group. Data are expressed as Mean±SE (P<0.05: * = alia vs syn; & = alia vs Aug).
Aug Lew syn alia
~ (#/mm) 40.51±1.31 35.83±0.67 32.215:1.87 20A2~2.04*&
D~ (~m) Vo.~ (urn~see) 10.475:0.12 386.13±9.09 10.115:0.18 421.035:13.18 10.575:0.16 460.115:14.28 11.385:0.28" 241.975:13.30"&
Pl(pl/sec.mm ~) 1345.005:57.29 1285.115:143.05 1335.555:84.56 594.505:99.31"&
In conclusion, profound alterations of the hepatic microcirculation, characterized by overt injury and impaired sinusoidal perfusion occur early during ~nte allograt~ rejection. We would suggest that this microcirculatory dysfunction may ultimately lead to graft failure. Supported by NU-Igrants DK02126 and DK38201.