Enhanced donor-specific alloreactivity occurs independently of immunosuppression in children with early liver rejection.
To determine whether early acute cellular rejection (ACR) is associated with sub-optimal immunosuppression in children with liver transplants (LTx).


METHODS
Twenty-five children with primary LTx after pre-transplant rabbit anti-thymocyte globulin (rATG), and steroid-free tacrolimus (TAC) were evaluated. Mitogen-stimulated T- and B-cell responses and mixed lymphocyte response to donor and third-party antigens were performed at several time points between two consecutive TAC doses. TAC concentrations (C) associated with half-maximal effect (EC(50)) on lymphocytes was determined by pharmacodynamic equations.


RESULTS
Mean age was 7.2 +/- 6.2 years, mean time to lymphocyte function studies was 25 +/- 19 days. Acute rejection occurred at a mean interval of 31 +/- 19 days after LTx. Rejectors (n = 16) demonstrated significantly higher EC(50) of TAC for the intra-cellular IFN-gamma in T cells (p = 0.005) and its CD8+ sub-population (p = 0.027) as well as the co-stimulatory/activation receptor CD54 on B cells (p = 0.0001). The response of recipient lymphocytes to donor antigen was significantly higher in rejectors, compared with non-rejectors (p = 0.015). The patient groups demonstrated no differences in third-party MLR, or in C of TAC.


CONCLUSIONS
Independent of the amount of immunosuppressant, ACR of liver allografts in children is associated with enhanced donor-specific alloreactivity. This is accompanied by a cytotoxic T-cell sub-population with increased requirement for TAC.
Sindhi
Rakesh
R
Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA. rakesh.sindhi@chp.edu
Magill
Amy
A
Bentlejewski
Carol
C
Abdullah
Ali
A
Tresgaskes
Mary
M
Seward
Joseph
J
Janosky
Janine
J
Zeevi
Adriana
A
D000293:Adolescent; D000818:Animals; D000941:Antigens / Q000737:chemistry; D018941:Antigens, CD19 / Q000096:biosynthesis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D005260:Female; D005434:Flow Cytometry; D006084:Graft Rejection; D006801:Humans; D007108:Immune Tolerance; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007223:Infant; D007371:Interferon-gamma / Q000378:metabolism; D008099:Liver / Q000276:immunology; D016031:Liver Transplantation / Q000379:methods*; D016131:Lymphocyte Subsets; D008214:Lymphocytes / Q000276:immunology; D008297:Male; D011817:Rabbits; D013154:Spleen / Q000166:cytology; D013256:Steroids / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology; D016559:Tacrolimus / Q000378:metabolism; D013997:Time Factors; D014019:Tissue Donors
D000941:Antigens; D018941:Antigens, CD19; D007166:Immunosuppressive Agents; D013256:Steroids; D007371:Interferon-gamma; D016559:Tacrolimus