Role of human and porcine MHC DRB1 alleles in determining the intensity of individual human anti‐pig T‐cell responses

Abstract

Background Differences in quality and strength of immune responses between individuals are mainly due to polymorphisms in major histocompatibility complex (MHC) molecules. Focusing on MHC class‐II, we asked whether the intensity of human anti‐pig T‐cell responses is influenced by genetic variability in the human HLA‐DRB1 and/or the porcine SLA‐DRB1 locus. Methods ELISpot assays were performed using peripheral blood mononuclear cells (PBMCs) from 62 HLA‐DRB1‐typed blood donors as responder and the porcine B cell line L23 as stimulator cells. Based on the frequency of IFN‐γ‐secreting cells, groups of weak, medium, and strong responder individuals were defined. Mixed lymphocyte reaction (MLR) assays were performed to study the stimulatory capacity of porcine PBMCs expressing different SLA‐DRB1 alleles. Results Concerning the MHC class‐II configuration of human cells, we found a significant overrepresentation of HLA‐DRB1*01 alleles in the medium/strong responder group as compared to individuals showing weak responses to stimulation with L23 cells. Evaluation of the role of MHC class‐II variability in porcine stimulators revealed that cells expressing SLA‐DRB1*06 alleles triggered strong proliferation in approximately 70% of humans. Comparison of amino acid sequences indicated that strong human anti‐pig reactivity may be associated with a high rate of similarity between human and pig HLA/SLA‐DRB1 alleles. Conclusion Variability in human and porcine MHC determines the intensity of individual human anti‐pig T‐cell responses. MHC typing and cross‐matching of prospective recipients of xenografts and donor pigs could be relevant to select for donor‐recipient combinations with minimal anti‐porcine immunity.

Humanization of Immunodeficient Animals for the Modeling of Transplantation, Graft Versus Host Disease, and Regenerative Medicine

“… 216 Human lymphocytes can recognize porcine MHC molecules and respond at similar levels to human allogenic MHC proteins. 218 , 219 The homology between human and porcine MHC molecules means that antibodies against HLA class II antigens have a propensity to also bind swine leukocyte antigen class II antigens. In the context of future immune humanization of immunodeficient pigs, it is important to point out that porcine SIRPα binds to human CD47 and thus provides inhibition of pig macrophage phagocytosis of human leukocytes.…”

Xenotransplantation literature update, July/August 2019

“…Looking deeper into antigen presentation itself and providing insight into the deviations seen between donors in co‐culture studies, Hundrieser et al focused their research on MHC‐II, studying human leukocyte antigen (HLA) and swine leukocyte antigen (SLA) polymorphisms at the human HLA‐DRB1 and the porcine SLA‐DRB1 locus, and reviewing their effects on individual immune responses. The MHC system is known to be highly polymorphic, and while the high level of homology between HLA and SLA allows human T‐cell receptor (TcR) to bind to SLA molecules and trigger T‐cell activation, SLA can also trigger anti‐HLA antibodies .…”

“…The MHC system is known to be highly polymorphic, and while the high level of homology between HLA and SLA allows human T‐cell receptor (TcR) to bind to SLA molecules and trigger T‐cell activation, SLA can also trigger anti‐HLA antibodies . However, TcRs are sensitive to minimal structural changes in MHC/peptide complexes and to evaluate the effects of different SLA and HLA haplotypes and discover weak stimulatory combinations, and Hundrieser et al performed ELISpot and MLR assays on HLA‐DRB1‐typed PBMC donors with porcine B cell line L23 cells to determine a weak, medium, or strong response based on the frequency of IFN‐y secretion . In accompaniment to this, MLR assays determined the ability of differing SLA‐DRB1 allele expressing PBMC to stimulate the HLA‐DRB1‐typed human donor cells .…”

“…However, TcRs are sensitive to minimal structural changes in MHC/peptide complexes and to evaluate the effects of different SLA and HLA haplotypes and discover weak stimulatory combinations, and Hundrieser et al performed ELISpot and MLR assays on HLA‐DRB1‐typed PBMC donors with porcine B cell line L23 cells to determine a weak, medium, or strong response based on the frequency of IFN‐y secretion . In accompaniment to this, MLR assays determined the ability of differing SLA‐DRB1 allele expressing PBMC to stimulate the HLA‐DRB1‐typed human donor cells . The work of Hundrieser et al revealed a high HLA‐DRB1*01 allele presence in the PBMC donors that had a medium to strong response to L23 cells .…”

“…In the previous issue of Xenotransplantation, Zhou et al provided an updated review of the complement system in xenograft rejection; Hundrieser et al discuss how porcine and human MHC‐II polymorphisms influence donor reactivity; Ladowski et al seek to eliminate all donor xenoantigens; Cooper et al review a 9 gene alteration of porcine donors for clinical xenotransplantation; Zhou et al present a strategy to monitor xenograft rejection with porcine cDNA biomarkers; Zafar et al provide further research into reducing porcine islet immunoreactivity; Li et al studied the cold storage of porcine hepatocyte spheroids; Iizuka et al deep dive into porcine C‐peptide pharmacokinetics; and, finally, Zheng et al, Zhao et al, and Yoon et al provide updates in corneal xenotransplantation.…”