PDCD1 SNPs and alloimmune transplant outcomes: mechanistic basis and human evidence across solid organ transplantation and allogeneic hematopoietic stem cell transplantation

Background

The programmed cell death 1 gene (PDCD1) encodes programmed death-1 protein (PD-1), an inhibitory immune-checkpoint receptor that regulates peripheral tolerance and alloimmune activation. Scope: This narrative review synthesizes mechanistic and human evidence linking PDCD1 single-nucleotide polymorphisms (SNPs) to transplant-related alloimmune outcomes. In solid organ transplantation (SOT), outcomes are framed mainly as rejection-related endpoints, whereas in allogeneic hematopoietic stem cell transplantation (allo-HSCT), bone marrow transplantation (BMT), and cord blood transplantation (CBT), graft-versus-host disease, relapse, infection, survival, mortality, and engraftment are treated as clinically distinct endpoints rather than SOT-like rejection. Evidence synthesis: PDCD1 variants encompass regulatory, intronic, coding, and 3'UTR loci with potentially different biological consequences. For some variants, experimental studies support effects on transcriptional regulation or transcription-factor binding, whereas for others the biological significance remains uncertain and may depend on linkage disequilibrium with neighboring regulatory alleles. Human transplant studies remain limited and heterogeneous: SOT studies are largely negative or inconclusive, whereas allo-HSCT/CBT studies report associations with GVHD, relapse, infection, survival, mortality, or engraftment, most of which await independent replication. Accordingly, the reported genotype-outcome relationships should be regarded as associations rather than evidence of causality, and the current evidence is insufficient to support validated clinical prediction based on individual PDCD1 variants.