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Progressive liver pathology in long term survivors of paediatric liver transplantation
246A
AASLD ABSTRACTS
HEPATOLOGYOctober 2001
289
290
IMPACT OF LYMPHOPROLIFERATIVE DISORDERS AFTER PEDIATRIC LIVER TRANSPLANT: A SINGLE CENTER TEN-YEAR EXPERIENCE.
SAFETY A N D EFFICACY OF RITUXlMAB IN PEDIATRIC LIVER TRANSPLANT PATIENTS W I T H POSTTRANSPLANT LYMPHOPROLIFERATIVE DISORDER (PTLD). Murat Kilic, Saul J Karpen, Philip Seu, Barbara
Regino P Gonzalez-Peralta, Cheryl W McGinnis, Donald A Novak, Christopher D Jolley, Pediatric Liver Transplant Program, Univ of Florida, Gainesville, FL; Suzanne Skoda-Smith, Pediatric Immunology, Univ of Florida, Gainesville, FL; Elizabeth L Mackay, Pediatric Liver Transplant Program, Univ of Florida, Gainesvtlle, FL; Gregory V Scott, Dept of Pathology, Univ of Florida, Gainesville, FL; Max R Langham Jr., Pediatric Liver Transplant Program, Univ of Florida, Gainesville, FL PURPOSE Lymphoproliferative disorders are increasingly important in the long-term management of children after liver transplant and have been associated with poor clinical outcomes. AIM To analyze the clinical outcomes of children with lymphoproliferative disorders after liver transplant. METHODS We reviewed the charts of 120 children ( < 18 yrs old) who had undergone liver transplantation in our center between 1990-2000. RESULTS Six of the 120 patients (5%) developed post-transplant lymphoproliferative disorder based on clinical, virologic and histologic criteria (age at transplant 4 mo-18 yrs, Male:Female 3:3, White:African-American:Hispanic 3:2:1). Lymphoproliferatire disorders were diagnosed at a mean of 27 mo after transplant (range 1-84 too): Burkitt's lymphoma (n= 1), iris tumor (n= 1), hepatic lymphoid infiltration (n=2), acute lymphocytic leukemia (n= 1), and generalized adenopathy ( n = l ) . At the time of diagnosis, all 6 patients were receiving calcineurin inhibitors and corticosteroids, initiated immediately pre-transplant. Two children were receiving anti-metabolites (started after acute rejection) and OKT3 was used in 2 patients (steroid-resistant rejection). None of the patients received antibody induction therapy. At transplant, none of the patients had serologic evidence of active Epstein-Barr virus (EBV) infection. Treatment of post-transplant lymphoproliferative disorder included reduction of immunosuppression in aI1 patients (temporarily discontinued in 1), and antiviral (n=5) and immunoglobulin (n=2) therapy. Four of the 6 patients are alive (mean follow-up after diagnosis of lymphoproliferative disorder 25 too, range 8-38 too). Of these patients, EBV levels are low in 3 ( < 100 EBV genomes/105 lymphocytes) and persistently high in 1 (>1000 EBV genomes/105 lymphocytes). AlI patients have been successfully managed on low-dose immunosuppression without graft loss. Of the 2 deaths, one was directly related to posttransplant lymphoproliferative disorder and one to pneumococcal sepsis. CONCLUSIONS The incidence of post-transplant lymphoproliferative disorder in our center was Iow (5%) and was associated with low mortality rate (16%) and excellent graft survival (100%) without recurrence of active disease.
Savoldo, Helen Heslop, Cliona Rooney, John A Goss, Baylor Coil of Medicine, Houston, TX BACKGROUND: PTLD is a complication of pediatric orthotopic liver transplantation (POLT). Conventional treatment of PTLD includes withdrawaI of immunosup ression, leaving the pt at risk of allograft rejection and loss or cytotoxic chemotherapy with potential for toxic anPdPsepticcomplications. Rituximab anti CD-20 mAb, introduced as treatment of recurrent E cell |ymphoma,has also been used as a second-line treatment in recalcitrant PTLD with a 60% rate of response and potentially serious side effects. The alto of this study was to evaluate safety and efficacy of Rituximab as a first line treatment for early PTLD in POLT pts. MATERIALAND METHODS: Between 7/1/99 and 5/1/01,10 EBV seronegative children received EBV sero ositive afiograRs. Following POLT alI pts were evaluated for the development of EBV infection and PTLD by physica~e~xaminationand serial quantitative real time PCR EBV DNA levels. 8 prs had EBVDNA levels exceeding 1000 copies/mg on 2 consecutive evaluations and underwent radiographic evaluation in an attempt to identify lymphadenOmar~rs,athyor other evidence of PTLD. 4 pts had histologically confirmed PTLD, and were studied for EBV replieative T and B cell phenotypes by immunohistoehemistry, and CD 20 quantification by flow eytometry. After confirming CD20 posiavity the pts were treated with Rimximab 375 mg/ m2/wk i.v. for 4 cycles without withdrawal Of ealcineurin blockade based immunosuppression. RESULTS:All 4 pts completed the course of Rituximab withom adverse event. Imme~ate clinical response was seen in all 4 pts including resolution of fever, diarrhea, and fatigue. As shown in the graph below, EBV DNA levels were reduced with the administration of Pdtuximab and correlated with the resolution of clinical symptoms. All radiographic evidence of PTLD, including a submueosal duodenal mass (1 pt) and an infiltrative tiulmonar F mass (1 pt) resolved with Pdtuximab. Peripheral blood flow cytometry demonstrated depletion orB cells for 3 months following Rituximab while immunoglobufin levels were not affected. Calcineurin inhibitor-based immunosuppression was maintained in all patients and no a~ograft dys~uncti~n was ~ted. A~lpts are a~iveand we~ with~m eviden~e ~f recurr~nt ~TLD serious infection, or allograft rejection (median follow-up 6 mos, range 2-16 too). CONCLUSION: Rimximab is a safe and effective mode of therapy for the POLT pt with PTLD. In addition to providing superior clirdcal responses, it allows the maintenance of calcineurin inhibitor-based immunosuppression, while preventing allograR dysfunction.
"~A
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291
292
PROGRESSIVE LIVER PATHOLOGY IN LONG TERM SURVIVORS OF PAEDIATRIC LIVER TRANSPLANTATION. Helen M Evans, The University
TACROLIMUS OFFERS TOTAL ABSENCE OF CHRONIC REJECTION IN PEDIATRIC LIVER TRANSPLANT RECIPIENT: FOELOWUP OF 7-10 YEARS. Ashok B Jain, George Mazariegos, Randeep S Kashyap, John J Fung,
of Birmingham, Birmingham Uk; Patrick J McKiernan, Susan V Beath, Jean De Ville de Goyet, The Liver Unit, Birmingham Children's Hospital, Birmingham Uk; Stefan G Hubscher, The University of Birmingham, Birmingham Uk; Deirdre A Kelly, The Liver Unit, Birmingham Children's Hospital, Birmingham Uk Introduction: Five year survival foUowingpaediatric liver transplantation (OLT) is -->85%
but the long term histological outcome of allografts is unknown. We previously reported that at 5 yrs post OLT, 77% of liver biopsies were abnormal, with 48% demonstrating graft hepatitis of unknown aettology.1~[Aim: To eValuate graft histology at 1, 5 and 10 yrs post OLT and correlate with liver biochemistry and autoantibody (Abs) results 1o determine fPrOtentialpredictive and aetiological factors.q[Methods: A retrospective review of histology om protocol biopsies at 1, 5 and 10 yrs post OLT was performed and compared with standard liver biochemistry and immunological markers (ANA (1 in 25), SMA (1 in 40), LKM (1 in 40) and AMA (1 in 40) and immunoglobulins). Logistic regression was used to identify factors which correlated with abnormal histology.~ Results: 159 children (78M; 8IF) underwent OLT and had graft survival of -> 5 yrs. Immunosuppression was cyclosporin, corticosteroids and azathioprine, with cyclosporin monotherapy after 12 months. Histological data were available from 124 (6 IM; 63F) (78%) patients (Table 1). At 1 yr post OLT, abnormal liver biochemistry correlated with abnormal allograft histology, but not at 5 and 10 yrs. There was a statistically significant increase in graft hepatitis and fibrosis/ cirrhosis aL 5 and 10 yrs (p<0.05). There was a correlation between graft hepatitis and positive autoantibodies at 5 and 10 yrs (p<0.03) but hypergammaglobulinaemia was present in only 4 children at 5 yrs.~[Conclusions: The incidence of abnormal graft histology increased progressively between 1 and 10 yrs. At 1 yr post OLT, abnormal liver biochemistry correlated with abnormal allograft histology, but not at 5 and 10 yrs post OLT. Liver biochemistry was not predictive of graft hepatitis. The development of graft hepatitis was associated with positive ANA and SMA,which were positive in all children with hepatitis by 10 yrs. The aetiology of graft hepatitis has yet to be explained but may have an immunological basis.~ Reference: 1. HM Evans et al. Histology of Liver Allografts Five Years Following Paediatric Liver Transplantation. Hepatology 2000; 32 (4 Suppl 2); 227A
Table ~: Histological results year (n=1t 1) 5 years (n=124) 10 years (n=32) Histologyl Pos Abs¶ Histology~ Pos Abs¶ Histology¶ Pos Abs¶ No, No.(%) No.(%) ,, So.(%) No.(%) No.(%) (%) , Normal 65 (59) 0 35 (28) O 6 (19) 0 Hepatitis 26 (23) 7 (27) 4t (33) 34 (83) 12 (38) 12 (100) Hep & tib 5(5) 1 (20) 2t (17) 15(71) 5(16) 4(80) Fibrosis 3 (3) 0 18 (15) 4 (22) 7 (22) 4 (57) Rejection 8 (7) O 6 (5) 1 (17) 2 (6) 1 (50) Other 4 (4) 0 3 (2) I (33) 0 0
Thomas StarzI, Jorge Reyes, T E Starzl Transplantation Institute, Pittsburgh, PA Introduction: Chronic rejection is a significant cause of graft failure after successful solid organ transplantation. There is no satisfactory remedy for prevention or treatment and often leads to graft failure, requiring retransplantation, that carries higher risk to the patient than primary transplantation. Tacrolimus was introduced in pediatric primary transplantation about 12 years ago at our center. Aim of the present study is to examine the incidence of chronic rejection in pediatric (age < 18 years) primary liver transplantation under tacrolimus based immunosuppression in the long term. Material Method: Between Oct 89 to Dec 92, 166 children mean 5.9 + 2.9 years received cadaveric liver transplantation under tacrolimus based immunosuppression. All children were followed up to March 2000. Mean follow up 9.0 + 0.8 (range 7.4 to10.4; median 9.2) years. All the biopsies performed during this time period were reviewed for evidence of chronic rejection using Banffs criteria. Also patients who either died or received retransplantation were evaluated for chronic rejection. Results: Survival:10 year actuarial patient survival is 84.9% and graft survival 80.1%. Causes of Death: Twenty five children died during the follow up period sepsis (8), Intraoperative (4), CNS complication (5), Liver failure (PNF; 4), PTLD (2), recurrence malignancy (1)~ and post operative subclavian bleeding (1). Causes of Retransplant: During the follow up period 18(10.8%) children received retransplantation for primary non function (9), hepatic artery thrombosis (6), and viral hepatitis (3; EBV, HCV, Adeno virus). Liver Biopsy: 535 liver biopsies (mean 3.2 + 0.8 per patient) were available (including 18-explanted liver allograft). Incidence of Chronic Rejection: None of the liver biopsies had any evidence of chronic allograft rejection. 15 children who died without retransplantation with original graft neither had any evidence on Iiver biopsy when performed before death, or any biochemical evidence of chronic rejection. Their current Liver function: Mean T Bili, AST, ALT GGTP, ALKPo4 is 0.7rag/all, 39.3u~, 39u/1, 58 u/l, and 245u/1 respectively. Renal Function:Mean BUN and Creat is 15.7mg/dl and 1.6rag/d1 respectively. Immuuosuppression: Mean Tacrolimus dose is 3.5rag/day, mean tacrolimus level is 6ng/ml, mean prednisone dose 6rag/day. Conclusion: 10 year actuarial, patient survival is 85% and graft survival 80%. None of the liver biopsies or explanted allograft showed any evidence of chronic rejection Tacrolimus thus not only has efficacy in reducing acute episodes of rejection severity of acute rejection and steroid resistant acute rejection but also has unique property to prevent chronic rejection in pediatric liver allograft in long term follow up to 10 years.
AASLD ABSTRACTS
HEPATOLOGYOctober 2001
289
290
IMPACT OF LYMPHOPROLIFERATIVE DISORDERS AFTER PEDIATRIC LIVER TRANSPLANT: A SINGLE CENTER TEN-YEAR EXPERIENCE.
SAFETY A N D EFFICACY OF RITUXlMAB IN PEDIATRIC LIVER TRANSPLANT PATIENTS W I T H POSTTRANSPLANT LYMPHOPROLIFERATIVE DISORDER (PTLD). Murat Kilic, Saul J Karpen, Philip Seu, Barbara
Regino P Gonzalez-Peralta, Cheryl W McGinnis, Donald A Novak, Christopher D Jolley, Pediatric Liver Transplant Program, Univ of Florida, Gainesville, FL; Suzanne Skoda-Smith, Pediatric Immunology, Univ of Florida, Gainesville, FL; Elizabeth L Mackay, Pediatric Liver Transplant Program, Univ of Florida, Gainesvtlle, FL; Gregory V Scott, Dept of Pathology, Univ of Florida, Gainesville, FL; Max R Langham Jr., Pediatric Liver Transplant Program, Univ of Florida, Gainesville, FL PURPOSE Lymphoproliferative disorders are increasingly important in the long-term management of children after liver transplant and have been associated with poor clinical outcomes. AIM To analyze the clinical outcomes of children with lymphoproliferative disorders after liver transplant. METHODS We reviewed the charts of 120 children ( < 18 yrs old) who had undergone liver transplantation in our center between 1990-2000. RESULTS Six of the 120 patients (5%) developed post-transplant lymphoproliferative disorder based on clinical, virologic and histologic criteria (age at transplant 4 mo-18 yrs, Male:Female 3:3, White:African-American:Hispanic 3:2:1). Lymphoproliferatire disorders were diagnosed at a mean of 27 mo after transplant (range 1-84 too): Burkitt's lymphoma (n= 1), iris tumor (n= 1), hepatic lymphoid infiltration (n=2), acute lymphocytic leukemia (n= 1), and generalized adenopathy ( n = l ) . At the time of diagnosis, all 6 patients were receiving calcineurin inhibitors and corticosteroids, initiated immediately pre-transplant. Two children were receiving anti-metabolites (started after acute rejection) and OKT3 was used in 2 patients (steroid-resistant rejection). None of the patients received antibody induction therapy. At transplant, none of the patients had serologic evidence of active Epstein-Barr virus (EBV) infection. Treatment of post-transplant lymphoproliferative disorder included reduction of immunosuppression in aI1 patients (temporarily discontinued in 1), and antiviral (n=5) and immunoglobulin (n=2) therapy. Four of the 6 patients are alive (mean follow-up after diagnosis of lymphoproliferative disorder 25 too, range 8-38 too). Of these patients, EBV levels are low in 3 ( < 100 EBV genomes/105 lymphocytes) and persistently high in 1 (>1000 EBV genomes/105 lymphocytes). AlI patients have been successfully managed on low-dose immunosuppression without graft loss. Of the 2 deaths, one was directly related to posttransplant lymphoproliferative disorder and one to pneumococcal sepsis. CONCLUSIONS The incidence of post-transplant lymphoproliferative disorder in our center was Iow (5%) and was associated with low mortality rate (16%) and excellent graft survival (100%) without recurrence of active disease.
Savoldo, Helen Heslop, Cliona Rooney, John A Goss, Baylor Coil of Medicine, Houston, TX BACKGROUND: PTLD is a complication of pediatric orthotopic liver transplantation (POLT). Conventional treatment of PTLD includes withdrawaI of immunosup ression, leaving the pt at risk of allograft rejection and loss or cytotoxic chemotherapy with potential for toxic anPdPsepticcomplications. Rituximab anti CD-20 mAb, introduced as treatment of recurrent E cell |ymphoma,has also been used as a second-line treatment in recalcitrant PTLD with a 60% rate of response and potentially serious side effects. The alto of this study was to evaluate safety and efficacy of Rituximab as a first line treatment for early PTLD in POLT pts. MATERIALAND METHODS: Between 7/1/99 and 5/1/01,10 EBV seronegative children received EBV sero ositive afiograRs. Following POLT alI pts were evaluated for the development of EBV infection and PTLD by physica~e~xaminationand serial quantitative real time PCR EBV DNA levels. 8 prs had EBVDNA levels exceeding 1000 copies/mg on 2 consecutive evaluations and underwent radiographic evaluation in an attempt to identify lymphadenOmar~rs,athyor other evidence of PTLD. 4 pts had histologically confirmed PTLD, and were studied for EBV replieative T and B cell phenotypes by immunohistoehemistry, and CD 20 quantification by flow eytometry. After confirming CD20 posiavity the pts were treated with Rimximab 375 mg/ m2/wk i.v. for 4 cycles without withdrawal Of ealcineurin blockade based immunosuppression. RESULTS:All 4 pts completed the course of Rituximab withom adverse event. Imme~ate clinical response was seen in all 4 pts including resolution of fever, diarrhea, and fatigue. As shown in the graph below, EBV DNA levels were reduced with the administration of Pdtuximab and correlated with the resolution of clinical symptoms. All radiographic evidence of PTLD, including a submueosal duodenal mass (1 pt) and an infiltrative tiulmonar F mass (1 pt) resolved with Pdtuximab. Peripheral blood flow cytometry demonstrated depletion orB cells for 3 months following Rituximab while immunoglobufin levels were not affected. Calcineurin inhibitor-based immunosuppression was maintained in all patients and no a~ograft dys~uncti~n was ~ted. A~lpts are a~iveand we~ with~m eviden~e ~f recurr~nt ~TLD serious infection, or allograft rejection (median follow-up 6 mos, range 2-16 too). CONCLUSION: Rimximab is a safe and effective mode of therapy for the POLT pt with PTLD. In addition to providing superior clirdcal responses, it allows the maintenance of calcineurin inhibitor-based immunosuppression, while preventing allograR dysfunction.
"~A
Dr8
1 ~veek
I monIh
B ~eff~
~ 8
2 me~lhs
C
01
3 mo~ths
4 menths
8 moatl~
1~ men[hs
291
292
PROGRESSIVE LIVER PATHOLOGY IN LONG TERM SURVIVORS OF PAEDIATRIC LIVER TRANSPLANTATION. Helen M Evans, The University
TACROLIMUS OFFERS TOTAL ABSENCE OF CHRONIC REJECTION IN PEDIATRIC LIVER TRANSPLANT RECIPIENT: FOELOWUP OF 7-10 YEARS. Ashok B Jain, George Mazariegos, Randeep S Kashyap, John J Fung,
of Birmingham, Birmingham Uk; Patrick J McKiernan, Susan V Beath, Jean De Ville de Goyet, The Liver Unit, Birmingham Children's Hospital, Birmingham Uk; Stefan G Hubscher, The University of Birmingham, Birmingham Uk; Deirdre A Kelly, The Liver Unit, Birmingham Children's Hospital, Birmingham Uk Introduction: Five year survival foUowingpaediatric liver transplantation (OLT) is -->85%
but the long term histological outcome of allografts is unknown. We previously reported that at 5 yrs post OLT, 77% of liver biopsies were abnormal, with 48% demonstrating graft hepatitis of unknown aettology.1~[Aim: To eValuate graft histology at 1, 5 and 10 yrs post OLT and correlate with liver biochemistry and autoantibody (Abs) results 1o determine fPrOtentialpredictive and aetiological factors.q[Methods: A retrospective review of histology om protocol biopsies at 1, 5 and 10 yrs post OLT was performed and compared with standard liver biochemistry and immunological markers (ANA (1 in 25), SMA (1 in 40), LKM (1 in 40) and AMA (1 in 40) and immunoglobulins). Logistic regression was used to identify factors which correlated with abnormal histology.~ Results: 159 children (78M; 8IF) underwent OLT and had graft survival of -> 5 yrs. Immunosuppression was cyclosporin, corticosteroids and azathioprine, with cyclosporin monotherapy after 12 months. Histological data were available from 124 (6 IM; 63F) (78%) patients (Table 1). At 1 yr post OLT, abnormal liver biochemistry correlated with abnormal allograft histology, but not at 5 and 10 yrs. There was a statistically significant increase in graft hepatitis and fibrosis/ cirrhosis aL 5 and 10 yrs (p<0.05). There was a correlation between graft hepatitis and positive autoantibodies at 5 and 10 yrs (p<0.03) but hypergammaglobulinaemia was present in only 4 children at 5 yrs.~[Conclusions: The incidence of abnormal graft histology increased progressively between 1 and 10 yrs. At 1 yr post OLT, abnormal liver biochemistry correlated with abnormal allograft histology, but not at 5 and 10 yrs post OLT. Liver biochemistry was not predictive of graft hepatitis. The development of graft hepatitis was associated with positive ANA and SMA,which were positive in all children with hepatitis by 10 yrs. The aetiology of graft hepatitis has yet to be explained but may have an immunological basis.~ Reference: 1. HM Evans et al. Histology of Liver Allografts Five Years Following Paediatric Liver Transplantation. Hepatology 2000; 32 (4 Suppl 2); 227A
Table ~: Histological results year (n=1t 1) 5 years (n=124) 10 years (n=32) Histologyl Pos Abs¶ Histology~ Pos Abs¶ Histology¶ Pos Abs¶ No, No.(%) No.(%) ,, So.(%) No.(%) No.(%) (%) , Normal 65 (59) 0 35 (28) O 6 (19) 0 Hepatitis 26 (23) 7 (27) 4t (33) 34 (83) 12 (38) 12 (100) Hep & tib 5(5) 1 (20) 2t (17) 15(71) 5(16) 4(80) Fibrosis 3 (3) 0 18 (15) 4 (22) 7 (22) 4 (57) Rejection 8 (7) O 6 (5) 1 (17) 2 (6) 1 (50) Other 4 (4) 0 3 (2) I (33) 0 0
Thomas StarzI, Jorge Reyes, T E Starzl Transplantation Institute, Pittsburgh, PA Introduction: Chronic rejection is a significant cause of graft failure after successful solid organ transplantation. There is no satisfactory remedy for prevention or treatment and often leads to graft failure, requiring retransplantation, that carries higher risk to the patient than primary transplantation. Tacrolimus was introduced in pediatric primary transplantation about 12 years ago at our center. Aim of the present study is to examine the incidence of chronic rejection in pediatric (age < 18 years) primary liver transplantation under tacrolimus based immunosuppression in the long term. Material Method: Between Oct 89 to Dec 92, 166 children mean 5.9 + 2.9 years received cadaveric liver transplantation under tacrolimus based immunosuppression. All children were followed up to March 2000. Mean follow up 9.0 + 0.8 (range 7.4 to10.4; median 9.2) years. All the biopsies performed during this time period were reviewed for evidence of chronic rejection using Banffs criteria. Also patients who either died or received retransplantation were evaluated for chronic rejection. Results: Survival:10 year actuarial patient survival is 84.9% and graft survival 80.1%. Causes of Death: Twenty five children died during the follow up period sepsis (8), Intraoperative (4), CNS complication (5), Liver failure (PNF; 4), PTLD (2), recurrence malignancy (1)~ and post operative subclavian bleeding (1). Causes of Retransplant: During the follow up period 18(10.8%) children received retransplantation for primary non function (9), hepatic artery thrombosis (6), and viral hepatitis (3; EBV, HCV, Adeno virus). Liver Biopsy: 535 liver biopsies (mean 3.2 + 0.8 per patient) were available (including 18-explanted liver allograft). Incidence of Chronic Rejection: None of the liver biopsies had any evidence of chronic allograft rejection. 15 children who died without retransplantation with original graft neither had any evidence on Iiver biopsy when performed before death, or any biochemical evidence of chronic rejection. Their current Liver function: Mean T Bili, AST, ALT GGTP, ALKPo4 is 0.7rag/all, 39.3u~, 39u/1, 58 u/l, and 245u/1 respectively. Renal Function:Mean BUN and Creat is 15.7mg/dl and 1.6rag/d1 respectively. Immuuosuppression: Mean Tacrolimus dose is 3.5rag/day, mean tacrolimus level is 6ng/ml, mean prednisone dose 6rag/day. Conclusion: 10 year actuarial, patient survival is 85% and graft survival 80%. None of the liver biopsies or explanted allograft showed any evidence of chronic rejection Tacrolimus thus not only has efficacy in reducing acute episodes of rejection severity of acute rejection and steroid resistant acute rejection but also has unique property to prevent chronic rejection in pediatric liver allograft in long term follow up to 10 years.