Evidence for a genetic predisposition towards acute rejection after kidney and simultaneous kidney-pancreas transplantation.
BACKGROUND
In vitro production of tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleukin 10 (IL-10), and transforming growth factor-beta (TGF-beta) correlate with their respective genetic polymorphisms. We analyzed the relationship between these genetic polymorphisms and posttransplant outcome.


METHODS
Using DNA polymerase chain reaction (PCR) technology, polymorphisms for TNF-alpha, IFN-gamma, IL-10, and TGF-beta were determined for 82 kidney (K) and 19 simultaneous kidney-pancreas (SKP) recipients. These results were analyzed with regard to the incidence of acute rejection (AR), and the timing and severity of the first AR episode.


RESULTS
A high TNF-alpha production phenotype correlated with recurrent acute rejection (AR) episodes (P<0.026). Compared with the low TNF-alpha production phenotype, more patients with the high production phenotype had a post-AR serum creatinine >2.0 mg/dl, but this was not statistically significant (64 vs. 35%, P=0.12). There was no relationship between TNF-alpha genotype and the time to first AR episode or incidence of graft loss. IFN-gamma production phenotype showed no correlation with any of these clinical outcome parameters. There was an increase in AR incidence as the IL-10 production phenotype increased (low, intermediate, high), but only in low TNF-alpha producer phenotypes (P=0.023).


CONCLUSIONS
Patients with a polymorphic cytokine genotype putatively encoding for high in vivo TNF-alpha production, and to a lesser extent IL-10 cytokine genotypes putatively encoding for higher levels of in vivo IL-10 production, had a worse clinical outcome regarding AR episodes. These data support the hypothesis that the strength of alloimmune responsiveness after transplantation in part is genetically determined.
Pelletier
R
R
Department of Surgery, Ohio State University College of Medicine, Columbus, 43210, USA.
Pravica
V
V
Perrey
C
C
Xia
D
D
Ferguson
R M
RM
Hutchinson
I
I
Orosz
C
C
D000208:Acute Disease; D000328:Adult; D016207:Cytokines / Q000235:genetics*; D004359:Drug Therapy, Combination; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006084:Graft Rejection / Q000453:epidemiology / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D015994:Incidence; D007371:Interferon-gamma / Q000235:genetics; D016753:Interleukin-10 / Q000235:genetics; D016030:Kidney Transplantation / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D016035:Pancreas Transplantation / Q000276:immunology*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012189:Retrospective Studies; D016212:Transforming Growth Factor beta / Q000235:genetics; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D016207:Cytokines; D007166:Immunosuppressive Agents; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007371:Interferon-gamma