Association of cytokine/costimulatory molecule polymorphism and allograft rejection: a comparative review

Abstract

One reason for genetic variations among human individuals is SNP which may confer diverse disease susceptibility or resistance in a population. Genetic variations in a key immunoregulatory agent can manifest various immunological responses, such as graft rejection. In fact, the outcome of organ transplantation can be impacted by several genetic causes including polymorphisms in genes encoding cytokines and costimulatory molecules in the donor or recipient. Thus, it can be helpful to contemplate the SNPs relating to these immunological determinants in order to achieve an improved transplantation therapy.

Keywords::

• costimulatory molecule
• cytokines
• gene polymorphisms
• transplantation

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• • Although Human Genome Project has searched the association of genetic regions with graft outcome, it is still interesting to explore the other genetic variation related to transplant rejection. It should be noted that while associations seem to apply to populations, they may not predict the definite outcome of graft in an individual.

• • Cytokine production has been shown to be different among individuals and consequently the susceptibility to graft rejection or acceptance may be possible.

• • While no association between TNF-α polymorphism and renal transplant outcome is definite, TNF-α^Hi producer genotype most likely impact the risk rejection in case of heart or liver rejection, as well as graft-versus-host disease (GVHD).

• • IL-10 low producer SNP is shown to increase the risk of renal or liver rejection. In lung transplantation, high producer SNP can protect the individuals from lung allograft rejection.

• • Among three isoforms of TGF-β, the level of TGF-β1 affected by seven SNPs, has more significance but may display inconsistent effects on different types of transplantation.

• • There has not been a study on the association between IL-17 G197A polymorphism (rs2275913) and allograft rejection in liver transplant patients, while in renal transplant ion, GG carriers and G allele showed a significantly more frequency in patients with acute rejection compared with patients without any sign of rejection.

• • IL-6^Hi producer genotype is mostly shown to be frequent in GVHD, kidney and liver rejection, but in cardiac allografts, no association was reported.

• • IFN-γ production is influenced by both IFN-γ gene and IFN-γ microsatellite SNPs; however, no similar results were obtained from various transplant studies.

• • Costimulatory molecules will certainly influence the graft outcome, but since there are several SNPs for them such as CTLA4 gene, it is hard to state its exact effect on graft outcome.

• • Although our group reported that CD28 CT genotype is more frequent in liver acute rejected patients, previous studies observed no association between CD28 SNP and transplantation outcome.

• • We found the higher frequency of PD-1.1 genotype in renal graft rejection. Also, the association between risks of CMV infection after kidney transplantation was previously reported by some researchers, while others disapproved such relations.