PDCD1 SNPs and alloimmune transplant outcomes: mechanistic basis and human evidence across solid organ transplantation and allogeneic hematopoietic stem cell transplantation
Abstract
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. Conclusion PDCD1 variation is biologically plausible as a context-dependent modifier of alloimmune outcomes, but no individual variant is ready for clinical risk prediction. Future studies should prioritize transplant-specific endpoints, paired donor-recipient analyses, and independent validation.