Background: Our previous studies demonstrated that cytokine gene polymorphisms are related to acute rejection in pediatric heart transplantation; a decreased tumor necrosis factor (TNF)-alpha production genotype combined with an increased or intermediate interleukin (IL)-10 production genotype was associated with the smallest incidence of acute rejection. The objective of this study was to determine whether cytokine genotypes TNF-alpha, IL-10, IL-6, interferon-gamma, and transforming growth factor beta were associated with acute persistent rejection after lung transplantation.
Methods: Cytokine genotyping was performed in 119 adult lung transplantation recipients who underwent surveillance transbronchial biopsies during their first year after transplantation. We categorized recipients with acute persistent rejection if they had 2 consecutive biopsy specimens at >/=Grade A2 despite anti-rejection treatment. We performed cytokine genotyping using the polymerase chain reaction-sequence specific primers technique, with a commercially available kit.
Results: We analyzed the IL-10 genotype in 116 patients. For the increased IL-10 production genotype, 7 of 20 patients (35%) were persistent rejecters. In comparison, 57 of 96 patients (59%) with intermediate or decreased IL-10 production genotype had acute persistent rejection (p = 0.046). For IL-10 haplotypes associated with intermediate IL-10 production, 30 of 45 patients with GCC/ACC haplotype (67%) had acute persistent rejection compared with 10 of 22 patients with GCC/ATA (45%). In the patients with intermediate IL-10 production, 17 of 22 (77%) with IL-10 GCC/ACC and IL-6 G/C had acute persistent rejection, whereas only 2 of 7 patients (29%) with IL-10 GCC/ATA and IL-6 G/G had acute persistent rejection (p = 0.018).
Conclusions: In lung transplant recipients, the increased IL-10 production genotype protects against acute persistent rejection when compared with the intermediate or decreased IL-10 production genotypes. The intermediate IL-10 production genotype in lung transplant recipients can be differentiated into 2 haplotype responses, with the GCC/ACC haplotype associated more with acute persistent rejection. In lung transplant recipients, the immunomodulatory effects of IL-6 are differentiated in the G/C and G/G alleles in conjunction with IL-10 haplotypes, with G/C being associated with more acute persistent rejection in conjunction with the IL-10 GCC/ACC haplotype. Future pharmacogenomic models may incorporate these associations with acute persistent rejection in lung transplant recipients to formulate individualized therapeutic regimens.