Introduction: The SIRPa-CD47 axis known as a self-tolerance mechanism through “don’t eat me signal” by phagocytotic myeloid cells. Recently, impact of SIRPa polymorphism has been reported to modulate APC activation in mice model. We have confirmed that human SIRPa V2 variant have higher binding capacity to CD47 and costimulatory effect on T cells. Herein, we demonstrated the impact of SIRPa genotype on immune response in the liver transplant (LT) cohort.
Methods: Genomic DNA obtained from peripheral blood was sequenced by Sanger method and NGS, targeted on SIRPa IgV domain bind to CD47. One hundred and ten recipient and donor pairs who underwent living donor LT were enrolled in this study to investigate the impact of SIRPa polymorphism on clinical outcomes. We administered a preconditioning regimen for B cell depletion to ABO-incompatible or sensitized patients (desensitized group, n=25). After LT, we employed an immunosuppressive protocol, including methylprednisolone and a calcineurin inhibitor (CNI), as a standard immune suppression (IS).
Results: Eighty-five recipient received standard IS after LT (standard IS group). To investigate clinical relevance, we categorized SIRPa genotype into 3 haplotypes (V1/V1, V1/V2, and V2/V2). We defined potential allo-response model of antigen presentation considering the mechanistic contribution of recipient and donor APC activation by bidirectional SIRPa-CD47 interaction and T cell activation by SIRPa inducing signal. In brief, V1 and V2 SIRPa induce weak (+) and strong (2+) signal, respectively. The model suppose APC express 2 type of SIRPa depend on genotype. The magnitude of donor APC presentation was calculated as the sum of signal from the donor APC activation status, which defined by the inhibitory input through donor SIRPa (2- in the case of V1/V1 genotype) and activating input induced by recipient SIRPa (3+ in the case of V1/V2), and T cell activation from donor SIRPa (4+ in case of V2/V2). Potential allo-response was the sum of donor and recipient APC presentation, that provide grade of magnitude from 4+ to 8+. We observed significantly lower acute rejection incidence in low response pairs (4+ and 5+) compared to high response pairs (6+, 7+, and 8+) in standard IS group (0/13(0%) vs 27/72(37.5%), p= 0.0009). Focusing on response against non-allogeneic antigen, which is protected by recipient APC, we observed that the incidence of blood stream infection (BSI) was stratified by the magnitude of presentation defined by SIRPa genotype in standard group (poorly vs intermediate vs highly protected recipient, 6/32 (18.8%) vs 17/43 (32.6%) vs 4/10 (40%)). In desensitized group who subject to T cell immunity rather than humoral immunity, SIRPa genotype more clearly stratified BSI incidence (poorly vs intermediate vs highly protected recipient, 0/9 (0%) vs 4/8 (50%) vs 7/8 (87.5%)).
Conclusions: Our findings indicate that recipient and donor SIRPa genotype impact on immune response after liver transplantation.