The Pig as a Model to Assess the Effect of Class II MHC Antigen Matching on Renal Allograft Survival

Pescovitz, Mark D.; Sachs, David H.

doi:10.1007/978-3-642-70367-6_32

Cited by 7 publications

(2 citation statements)

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“…The MHC of swine, termed SLA (3), has been shown to exhibit extensive similarities to its human counterpart in both structure and function (4). As a large animal model for studies of transplantation biology, our laboratory has developed a herd of partially inbred miniature swine in which three independent MHC haplotypes (SLAa, SLAC, and SLAd) and three intra-SLA recombinant haplotypes (SLA, SLA", and SLAh) are maintained (5,6).…”

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confidence: 99%

Structure of miniature swine class II DRB genes: conservation of hypervariable amino acid residues between distantly related mammalian species.

Gustafsson

Germana

Hirsch

et al. 1990

Proc. Natl. Acad. Sci. U.S.A.

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As part of our studies of the class II genes of miniature swine, we have isolated and characterized cDNA clones corresponding to DRB genes from two major histocompatibility complex homozygous strains. Comparison of the sequences of these clones to those of human DRB genes revealed a striking amino acid homology between the hypervariable residues of SLA-DRBC and the human DRBI-0101 allele. The percentage of differences in these residues between the pig DRBC allele and the human DRBI-OlO allele was significantly lower (29%) than that between the DRBI-OO0 allele and all other human alleles (average, 66.2%). This similarity was not seen in a comparison of the number of silent substitutions, by which the swine DRBC and the human DRB-0101 differed. Since phenotypic selection operates at the level of protein products rather than nucleotide sequences, these data suggest the existence of selective mechanisms that have resulted in similar hypervariable regions in certain alleles even in these widely disparate species. Consistent with this hypothesis, an examination of available murine and bovine class II sequences revealed a homology in hypervariable residues between the human DRBI-1401 allele and the mouse Eps allele as well as a cow DRB allele. Consideration of these data along with intraspecies allelic sequence comparisons suggests that at least some of the interspecies similarities have emerged as the result of convergent evolution, possibly as the result of a need to react to common pathogens.The major histocompatibility complex (MHC) contains genes encoding cell-surface molecules playing a pivotal role in antigen presentation to T cells (1). The MHC of mammals is one of the most polymorphic genetic systems known, in terms of both number of alleles and structural differences between alleles. The MHC genes are divided into two classes, I and II, of which the class II genes encode two separate chains, a and A, forming a dimer on the cell surface.Almost all of the polymorphism in the class II A3 chains is concentrated in <20 amino acid residues, all of which have been hypothesized to be in direct contact with, or in close proximity to, the antigen and/or the T-cell receptor during antigen presentation (2).The MHC of swine, termed SLA (3), has been shown to exhibit extensive similarities to its human counterpart in both structure and function (4). As a large animal model for studies of transplantation biology, our laboratory has developed a herd of partially inbred miniature swine in which three independent MHC haplotypes (SLAa, SLAC, and SLAd) and three intra-SLA recombinant haplotypes (SLA, SLA", and SLAh) are maintained (5, 6). Studies of vascular grafts in these animals have shown that long-term tolerance can be obtained without exogenous immunosuppression by matching for SLA class II loci only, despite differences at class I and numerous minor loci (7). Because these results suggest the possibility of modifying transplantation immunity by genetic engineering of SLA class II genes, we have recently begun a de...

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confidence: 99%

Structure of miniature swine class II DRB genes: conservation of hypervariable amino acid residues between distantly related mammalian species.

Gustafsson

Germana

Hirsch

et al. 1990

Proc. Natl. Acad. Sci. U.S.A.

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“…Recently, inbred miniature swine have become available as experimetital atiitnals atid have gained much interest amongst immunologists and pharmacologists, because of close similarities between human and porcine tissues with regatd to itntnunologic, molecular and physiologic parameters (6)(7)(8)(9)(10). Moreover, miniature swine are now widely used in transplantation immunology, since they allow organ transplantation in animals of sitnilar size to humans, permit reproducible evaluation of the role of MHC class I and II molecules in rejection and/or tolerance and may be a future source of xetiografts for use in humans (II, 12).…”

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Characterization of cutaneous antigen presentation in partially inbred miniature swine

Grabbe

Fishbein

Sachs

et al. 1994

Experimental Dermatology

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MHC class I and II-defined, partially inbred miniature swine have recently become available as a large animal model in transplantation immunology. To investigate cutaneous immunocompetence in this model, cutaneous antigen presenting cell (APC) function was assessed. For morphologic analysis, punch biopsies were examined by electron microscopy. By this technique, epidermal Langerhans cells bearing typical Birbeck granules could be detected. For functional studies, epidermal cell (EC) suspensions were prepared from split thickness skin specimens. Using FACS analysis, freshly prepared epidermal cell suspensions contained 1.8-4.7% MHC class II-positive cells. These EC potently stimulated allogeneic nylon wool-enriched peripheral blood T cells in the primary mixed EC-lymphocyte reaction. For in vivo assessment of cutaneous APC function, EC suspensions enriched for or depleted of class II-positive EC were generated by panning of class II-positive EC using mouse anti-MHC class II antibodies and anti-mouse IgG-coated petri dishes. EC were then coupled to the hapten trinitrophenol (TNP) and injected s.c. into autologous or MHC-mismatched pigs twice at a one week interval. One week later, pigs were challenged by s.c.-injection of 0.5-1 x 10(7) TNP-coupled or uncoupled EC. Autologous unseparated EC as well as EC enriched for MHC class II-positive cells were able to sensitize naive animals against TNP, whereas neither TNP-coupled EC depleted of class II-positive APC, MHC-mismatched EC coupled to TNP, nor uncoupled EC induced immunity to TNP. Our data indicate that inbred miniature swine possess competent cutaneous APC which are able to induce cutaneous APC which are able to induce cutaneous immunity in a matter similar to Langerhans cells in murine or human skin.

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Class II genes of miniature swine

et al. 1988

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Class II genes of miniature swine have been characterized by restriction fragment length polymorphism (RFLP) analysis and by analysis of a series of clones isolated from a lymphocyte genomic library. For RFLP analysis, DNA samples from three independent major histocompatibility complex homozygous lines and three intra-MHC recombinant lines were digested with a variety of restriction enzymes and analyzed in Southern blots using human cDNA probes for DP, DQ, DR, and DZ alpha genes, and DP, DQ, DR, and DO beta genes. One, or at most two, unique fragments were detected by hybridization with each of the human alpha probes tested. In contrast, multiple bands (five to six for most enzymes examined) were detected by each of the human beta probes tested, the majority of which were found to cross-react with at least three of these probes under conditions of moderate stringency. Genomic DNA from the SLAc haplotype was cloned into an EMBL-3 bacteriophage vector, and the corresponding genomic library was screened with each of these human cDNA probes. The class II genes thereby isolated from this library showed characteristics consistent with those anticipated from the RFLP analysis. Thus, unique alpha genes were obtained which showed no evidence of cross-hybridization, while beta genes showed extensive cross-hybridization and were frequently detected in the library by more than one human beta gene probe. These data are consistent with early evolutionary divergence of alpha genes, prior to mammalian speciation, and with continuing evolution of beta genes, with possible shared usage of these genes by different alpha loci. The data also imply that alpha genes can readily be assigned to loci homologous to their human counterparts, but that beta genes will require further mapping and/or sequence analysis to confirm assignments.

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The Pig as a Model to Assess the Effect of Class II MHC Antigen Matching on Renal Allograft Survival

Cited by 7 publications

References 50 publications

Structure of miniature swine class II DRB genes: conservation of hypervariable amino acid residues between distantly related mammalian species.

Structure of miniature swine class II DRB genes: conservation of hypervariable amino acid residues between distantly related mammalian species.

Characterization of cutaneous antigen presentation in partially inbred miniature swine

Class II genes of miniature swine

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