Abstract:Many medical advancements-including improvements to anti-rejection therapies in transplantation and vaccine developmentrely on preclinical studies conducted in cynomolgus macaques (Macaca fascicularis). Major histocompatibility complex (MHC) class I and class II genes of cynomolgus macaques are orthologous to human leukocyte antigen complex (HLA) class I and class II genes, respectively. Both encode cell-surface proteins involved in cell recognition and rejection of non-host tissues. MHC class I and class II g… Show more
“…Based on the latest nomenclature update (see “ materials and methods section ” section), an overview is provided of the DQA1/DQB1 and DPA1/DPB1 lineage combinations that can be encountered in cynomolgus macaques (Fig. 5 ) (this study) (Otting et al 2017 ; Shortreed et al 2020 ). Fig.…”
Section: Resultsmentioning
confidence: 99%
“…The Mhc region in humans is by far the most intensively studied. The use of cynomolgus macaques as models in biomedical research, however, has intensified the research into their Mhc cluster over the past 10–15 years, resulting in substantial information on its organization and its repertoire (Budde et al 2010 ; Campbell et al 2009 ; Creager et al 2011 ; Doxiadis et al 2006 , 2010 , 2012 ; Karl et al 2017 ; Krebs et al 2005 ; O’Connor et al 2007 ; Otting et al 2012 , 2017 ; Pendley et al 2008 ; Saito et al 2012 ; Sano et al 2006 ; Shiina et al 2015 ; Shortreed et al 2020 ; van der Wiel et al 2015 ; Westbrook et al 2015 ).…”
Section: Introductionmentioning
confidence: 99%
“…The different genes might display differential levels of transcription, and those with high transcription levels are referred to as majors, whereas the lowly transcribed genes are referred to as minors (Otting 2005 ). For the Mafa-A region, each haplotype seems to contain at least one highly transcribed Mafa-A1 gene (major) (de Groot et al 2020 ; Otting et al 2005 ; Shortreed et al 2020 ). Occasionally, the presence of a second Mafa-A1 gene on a haplotype, encoding a different lineage, may occur.…”
Section: Introductionmentioning
confidence: 99%
“…The Mafa-B region, which is even more complex, can encode several B genes with a high transcription profile (majors), and haplotypes with up to seven major B genes have been described. However, the presence of one to three major B genes per haplotype is predominant (Budde et al 2010 ; Saito et al 2012 ; Shiina et al 2015 ; Shortreed et al 2020 ). On top of that, the region may comprise several B genes showing a low transcription profile (minors).…”
The major histocompatibility complex (MHC) plays a key role in immune defense, and the
Mhc
genes of cynomolgus macaque display a high degree of polymorphism. Based on their geographic distribution, different populations of cynomolgus macaques are recognized. Here we present the characterization of the
Mhc
class I and II repertoire of a large pedigreed group of cynomolgus macaques originating from the mainland north of the isthmus of Kra (
N
= 42). Segregation analyses resulted in the definition of 81 unreported
Mafa-A/B/DRB/DQ/DP
haplotypes, which include 32 previously unknown
DRB
regions. In addition, we report 13 newly defined
Mafa-A/B/DRB/DQ/DP
haplotypes in a group of cynomolgus macaques originating from the mainland south of the isthmus of Kra/Maritime Southeast Asia (
N
= 16). A relatively high level of sharing of
Mafa-A
(51%) and
Mafa-B
(40%) lineage groups is observed between the populations native to the north and the south of isthmus of Kra. At the allelic level, however, the
Mafa-A/B
haplotypes seem to be characteristic of a population. An overall comparison of all currently known data revealed that each geographic population has its own specific combinations of
Mhc
class I and II haplotypes. This illustrates the dynamic evolution of the cynomolgus macaque
Mh
c region, which was most likely generated by recombination and maintained by selection due to the differential pathogenic pressures encountered in different geographic areas.
Supplementary Information
The online version contains supplementary material available at 10.1007/s00251-021-01249-y.
“…Based on the latest nomenclature update (see “ materials and methods section ” section), an overview is provided of the DQA1/DQB1 and DPA1/DPB1 lineage combinations that can be encountered in cynomolgus macaques (Fig. 5 ) (this study) (Otting et al 2017 ; Shortreed et al 2020 ). Fig.…”
Section: Resultsmentioning
confidence: 99%
“…The Mhc region in humans is by far the most intensively studied. The use of cynomolgus macaques as models in biomedical research, however, has intensified the research into their Mhc cluster over the past 10–15 years, resulting in substantial information on its organization and its repertoire (Budde et al 2010 ; Campbell et al 2009 ; Creager et al 2011 ; Doxiadis et al 2006 , 2010 , 2012 ; Karl et al 2017 ; Krebs et al 2005 ; O’Connor et al 2007 ; Otting et al 2012 , 2017 ; Pendley et al 2008 ; Saito et al 2012 ; Sano et al 2006 ; Shiina et al 2015 ; Shortreed et al 2020 ; van der Wiel et al 2015 ; Westbrook et al 2015 ).…”
Section: Introductionmentioning
confidence: 99%
“…The different genes might display differential levels of transcription, and those with high transcription levels are referred to as majors, whereas the lowly transcribed genes are referred to as minors (Otting 2005 ). For the Mafa-A region, each haplotype seems to contain at least one highly transcribed Mafa-A1 gene (major) (de Groot et al 2020 ; Otting et al 2005 ; Shortreed et al 2020 ). Occasionally, the presence of a second Mafa-A1 gene on a haplotype, encoding a different lineage, may occur.…”
Section: Introductionmentioning
confidence: 99%
“…The Mafa-B region, which is even more complex, can encode several B genes with a high transcription profile (majors), and haplotypes with up to seven major B genes have been described. However, the presence of one to three major B genes per haplotype is predominant (Budde et al 2010 ; Saito et al 2012 ; Shiina et al 2015 ; Shortreed et al 2020 ). On top of that, the region may comprise several B genes showing a low transcription profile (minors).…”
The major histocompatibility complex (MHC) plays a key role in immune defense, and the
Mhc
genes of cynomolgus macaque display a high degree of polymorphism. Based on their geographic distribution, different populations of cynomolgus macaques are recognized. Here we present the characterization of the
Mhc
class I and II repertoire of a large pedigreed group of cynomolgus macaques originating from the mainland north of the isthmus of Kra (
N
= 42). Segregation analyses resulted in the definition of 81 unreported
Mafa-A/B/DRB/DQ/DP
haplotypes, which include 32 previously unknown
DRB
regions. In addition, we report 13 newly defined
Mafa-A/B/DRB/DQ/DP
haplotypes in a group of cynomolgus macaques originating from the mainland south of the isthmus of Kra/Maritime Southeast Asia (
N
= 16). A relatively high level of sharing of
Mafa-A
(51%) and
Mafa-B
(40%) lineage groups is observed between the populations native to the north and the south of isthmus of Kra. At the allelic level, however, the
Mafa-A/B
haplotypes seem to be characteristic of a population. An overall comparison of all currently known data revealed that each geographic population has its own specific combinations of
Mhc
class I and II haplotypes. This illustrates the dynamic evolution of the cynomolgus macaque
Mh
c region, which was most likely generated by recombination and maintained by selection due to the differential pathogenic pressures encountered in different geographic areas.
Supplementary Information
The online version contains supplementary material available at 10.1007/s00251-021-01249-y.
“…Using the triad data, we could use expected inheritance patterns for the alleles in each of the four exons to biologically validate the allele sets recovered from our QC measures, with the expectation that each allele found in an offspring’s genotype would also be found in at least one of its parents. This type of segregation analysis for MHC Class II haplotypes has been successfully performed in parent-offspring triads for several studies on pedigreed captive macaques [ 54 – 56 ].…”
The major histocompatibility complex (MHC) is an important gene complex contributing to adaptive immunity. Studies of platyrrhine MHC have focused on identifying experimental models of immune system function in the equivalent Human Leukocyte Antigen (HLA). These genes have thus been explored primarily in captive platyrrhine individuals from research colonies. However, investigations of standing MHC variation and evolution in wild populations are essential to understanding its role in immunity, sociality and ecology. Capuchins are a promising model group exhibiting the greatest habitat diversity, widest diet breadth and arguably the most social complexity among platyrrhines, together likely resulting in varied immunological challenges. We use high-throughput sequencing to characterize polymorphism in four Class II DR and DQ exons for the first time in seven capuchin species. We find evidence for at least three copies for DQ genes and at least five for DRB, with possible additional unrecovered diversity. Our data also reveal common genotypes that are inherited across our most widely sampled population, Cebus imitator in Sector Santa Rosa, Costa Rica. Notably, phylogenetic analyses reveal that platyrrhine DQA sequences form a monophyletic group to the exclusion of all Catarrhini sequences examined. This result is inconsistent with the trans-species hypothesis for MHC evolution across infraorders in Primates and provides further evidence for the independent origin of current MHC genetic diversity in Platyrrhini. Identical allele sharing across cebid species, and more rarely genera, however, does underscore the complexity of MHC gene evolution and the need for more comprehensive assessments of allelic diversity and genome structure.
Pancreatic islet transplantation efficacy for type 1 diabetes (T1D) management is limited by hypoxia-related graft attrition and need for systemic immunosuppression. To overcome these challenges, we developed the Neovascularized Implantable Cell Homing and Encapsulation (NICHE) device, which integrates direct vascularization for facile mass transfer and localized immunosuppressant delivery for islet rejection prophylaxis. Here, we investigated NICHE efficacy for allogeneic islet transplantation and long-term diabetes reversal in an immunocompetent, male rat model. We demonstrated that allogeneic islets transplanted within pre-vascularized NICHE were engrafted, revascularized, and functional, reverting diabetes in rats for over 150 days. Notably, we confirmed that localized immunosuppression prevented islet rejection without inducing toxicity or systemic immunosuppression. Moreover, for translatability efforts, we showed NICHE biocompatibility and feasibility of deployment as well as short-term allogeneic islet engraftment in an MHC-mismatched nonhuman primate model. In sum, the NICHE holds promise as a viable approach for safe and effective islet transplantation and long-term T1D management.
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