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Anthony W De Tomaso - One of the best experts on this subject based on the ideXlab platform.
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Balancing selection on Allorecognition genes in the colonial ascidian Botryllus schlosseri.
Developmental and Comparative Immunology, 2016Co-Authors: Marie L. Nydam, Emily E. Stephenson, Claire E. Waldman, Anthony W De TomasoAbstract:Abstract Allorecognition is the capability of an organism to recognize its own or related tissues. The colonial ascidian Botryllus schlosseri , which comprises five genetically distinct and divergent species (Clades A-E), contains two adjacent genes that control Allorecognition: fuhc sec and fuhc tm . These genes have been characterized extensively in Clade A and are highly polymorphic. Using alleles from 10 populations across the range of Clade A, we investigated the type and strength of selection maintaining this variation. Both fuhc genes exhibit higher within-population variation and lower population differentiation measures (F ST ) than neutral loci. The fuhc genes contain a substantial number of codons with >95% posterior probability of d N /d S > 1. fuhc sec and fuhc tm also have polymorphisms shared between Clade A and Clade E that were present prior to speciation (trans-species polymorphisms). These results provide robust evidence that the fuhc genes are evolving under balancing selection.
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Molecular evolution and in vitro characterization of Botryllus histocompatibility factor
Immunogenetics, 2015Co-Authors: Daryl A Taketa, Marie L. Nydam, Adam D. Langenbacher, Delany Rodriguez, Erin Sanders, Anthony W De TomasoAbstract:Botryllus schlosseri is a colonial ascidian with a natural ability to anastomose with another colony to form a vascular and hematopoietic chimera. In order to fuse, two individuals must share at least one allele at the highly polymorphic fuhc locus. Otherwise, a blood-based inflammatory response will occur resulting in a melanin scar at the sites of interaction. The single-locus genetic control of Allorecognition makes B. schlosseri an attractive model to study the underlying molecular mechanisms. Over the past decade, several candidate genes involved in Allorecognition have been identified, but how they ultimately contribute to Allorecognition outcome remains poorly understood. Here, we report our initial molecular characterization of a recently identified candidate allodeterminant called Botryllus histocompatibility factor ( bhf ). bhf , both on a DNA and protein level, is the least polymorphic protein in the fuhc locus studied so far and, unlike other known Allorecognition determinants, does not appear to be under any form of balancing or directional selection. Additionally, we identified a second isoform through mRNA-Seq and an EST assembly library which is missing exon 3, resulting in a C-terminally truncated form. We report via whole-mount fluorescent in situ hybridization that a subset of cells co-express bhf and cfuhc ^ sec . Finally, we observed BHF’s localization in HEK293T at the cytoplasmic side of the plasma membrane in addition to the nucleus via a nuclear localization signal. Given the localization data thus far, we hypothesize that BHF may function as a scaffolding protein in a complex with other Botryllus proteins, rather than functioning as an Allorecognition determinant.
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botryllus schlosseri Allorecognition tackling the enigma
Developmental and Comparative Immunology, 2015Co-Authors: Daryl A Taketa, Anthony W De TomasoAbstract:Allorecognition has been well-studied in the context of vertebrate adaptive immunity and recognition of the Major Histocompatibility Complex (MHC), which is the central event of vertebrate immune responses. Although Allorecognition systems have been identified throughout the metazoa, recent results have shown that there is no apparent conservation or orthologous relationship between the mechanisms underlying this phenomenon in different organisms. Thus the origin of the vertebrate adaptive immune system as well as these other complex recognition systems is a complete mystery. This review will focus on Allorecognition in Botryllus schlosseri, a basal chordate which undergoes a natural transplantation reaction following contact between two individuals, and, analogous to vertebrates, is controlled by a single locus. We will summarize each of the known candidate genes within this locus and their potential roles in Allorecognition, and speculate on how these findings may in fact be revealing potential functional relationships between disparate Allorecognition systems.
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Botryllus schlosseri Allorecognition: tackling the enigma ☆
Developmental and Comparative Immunology, 2014Co-Authors: Daryl A Taketa, Anthony W De TomasoAbstract:Allorecognition has been well-studied in the context of vertebrate adaptive immunity and recognition of the Major Histocompatibility Complex (MHC), which is the central event of vertebrate immune responses. Although Allorecognition systems have been identified throughout the metazoa, recent results have shown that there is no apparent conservation or orthologous relationship between the mechanisms underlying this phenomenon in different organisms. Thus the origin of the vertebrate adaptive immune system as well as these other complex recognition systems is a complete mystery. This review will focus on Allorecognition in Botryllus schlosseri, a basal chordate which undergoes a natural transplantation reaction following contact between two individuals, and, analogous to vertebrates, is controlled by a single locus. We will summarize each of the known candidate genes within this locus and their potential roles in Allorecognition, and speculate on how these findings may in fact be revealing potential functional relationships between disparate Allorecognition systems.
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Allorecognition, Germline Chimerism, and Stem Cell Parasitism in the Colonial Ascidian, Botryllus schlosseri
Biological Theory, 2014Co-Authors: Anthony W De TomasoAbstract:Many marine invertebrates have the ability to combine tissues with conspecifics and form chimeras. This ability is usually accompanied by the presence of a polymorphic self/non-self recognition system (Allorecognition) that allows integration of closely related individuals, but blocks interactions between those more distantly related. The presence of a discriminatory Allorecognition system suggests that there are costs and benefits to chimerism that are correlated to relatedness, but the nature of these costs and benefits is still poorly understood. Interestingly, Allorecognition is found throughout the animal kingdom, with examples in nearly all the multicellular phyla; however, the role of Allorecognition in these different species is not always clear. In addition, the molecular mechanisms underlying Allorecognition in different species are not related, suggesting a unique origin for each species. This brings up the question as to whether there is a universal need for self/non-self recognition processes among the metazoa, or if these systems evolve in response to different selective pressures. We are studying Allorecognition and chimerism in the colonial ascidian, Botryllus schlosseri. Allorecognition takes place at the tips of the extracorporeal vasculature, and can result in a parabiosis (fusion), or a rejection reaction that blocks vascular fusion. Fusion has both hypothesized benefits as well as well-documented costs. This article will focus on characterizing the costs and benefits of fusion and chimerism in Botryllus, and put them into the broader context of the role of Allorecognition in the metazoa.
Louise N Glass - One of the best experts on this subject based on the ideXlab platform.
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programmed cell death in neurospora crassa is controlled by the Allorecognition determinant rcd 1
Genetics, 2019Co-Authors: Asen Daskalov, Pierre Gladieux, Louise N Glass, Jens HellerAbstract:Nonself recognition following cell fusion between genetically distinct individuals of the same species in filamentous fungi often results in a programmed cell death (PCD) reaction, where the heterokaryotic fusion cell is compartmentalized and rapidly killed. The Allorecognition process plays a key role as a defense mechanism that restricts genome exploitation, resource plundering, and the spread of deleterious senescence plasmids and mycoviruses. Although a number of incompatibility systems have been described that function in mature hyphae, less is known about the PCD pathways in asexual spores, which represent the main infectious unit in various human and plant fungal pathogens. Here, we report the identification of regulator of cell death-1 (rcd-1), a novel Allorecognition gene, controlling PCD in germinating asexual spores of Neurospora crassa; rcd-1 is one of the most polymorphic genes in the genomes of wild N. crassa isolates. The coexpression of two antagonistic rcd-1-1 and rcd-1-2 alleles was necessary and sufficient to trigger cell death in fused germlings and in hyphae. Based on analysis of wild populations of N. crassa and N. discreta, rcd-1 alleles appeared to be under balancing selection and associated with trans-species polymorphisms. We shed light on genomic rearrangements that could have led to the emergence of the incompatibility system in Neurospora and show that rcd-1 belongs to a much larger gene family in fungi. Overall, our work contributes toward a better understanding of Allorecognition and PCD in an underexplored developmental stage of filamentous fungi.
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nlr surveillance of essential sec 9 snare proteins induces programmed cell death upon Allorecognition in filamentous fungi
Proceedings of the National Academy of Sciences of the United States of America, 2018Co-Authors: Pierre Gladieux, Louise N Glass, Jens Heller, Corinne Clave, Sven J SaupeAbstract:In plants and metazoans, intracellular receptors that belong to the NOD-like receptor (NLR) family are major contributors to innate immunity. Filamentous fungal genomes contain large repertoires of genes encoding for proteins with similar architecture to plant and animal NLRs with mostly unknown function. Here, we identify and molecularly characterize patatin-like phospholipase-1 (PLP-1), an NLR-like protein containing an N-terminal patatin-like phospholipase domain, a nucleotide-binding domain (NBD), and a C-terminal tetratricopeptide repeat (TPR) domain. PLP-1 guards the essential SNARE protein SEC-9; genetic differences at plp-1 and sec-9 function to trigger Allorecognition and cell death in two distantly related fungal species, Neurospora crassa and Podospora anserina Analyses of Neurospora population samples revealed that plp-1 and sec-9 alleles are highly polymorphic, segregate into discrete haplotypes, and show transspecies polymorphism. Upon fusion between cells bearing incompatible sec-9 and plp-1 alleles, Allorecognition and cell death are induced, which are dependent upon physical interaction between SEC-9 and PLP-1. The central NBD and patatin-like phospholipase activity of PLP-1 are essential for Allorecognition and cell death, while the TPR domain and the polymorphic SNARE domain of SEC-9 function in conferring allelic specificity. Our data indicate that fungal NLR-like proteins function similar to NLR immune receptors in plants and animals, showing that NLRs are major contributors to innate immunity in plants and animals and for Allorecognition in fungi.
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identification of Allorecognition loci in neurospora crassa by genomics and evolutionary approaches
Molecular Biology and Evolution, 2015Co-Authors: Jiuhai Zhao, Pierre Gladieux, Elizabeth Hutchison, Joanna Bueche, Charles Hall, Fanny Perraudeau, Louise N GlassAbstract:Understanding the genetic and molecular bases of the ability to distinguish self from nonself (Allorecognition) and mechanisms underlying evolution of Allorecognition systems is an important endeavor for understanding cases where it becomes dysfunctional, such as in autoimmune disorders. In filamentous fungi, Allorecognition can result in vegetative or heterokaryon incompatibility, which is a type of programmed cell death that occurs following fusion of genetically different cells. Allorecognition is genetically controlled by het loci, with coexpression of any combination of incompatible alleles triggering vegetative incompatibility. Herein, we identified, characterized, and inferred the evolutionary history of candidate het loci in the filamentous fungus Neurospora crassa. As characterized het loci encode proteins carrying an HET domain, we annotated HET domain genes in 25 isolates from a natural population along with the N. crassa reference genome using resequencing data. Because Allorecognition systems can be affected by frequency-dependent selection favoring rare alleles (i.e., balancing selection), we mined resequencing data for HET domain loci whose alleles displayed elevated levels of variability, excess of intermediate frequency alleles, and deep gene genealogies. From these analyses, 34 HET domain loci were identified as likely to be under balancing selection. Using transformation, incompatibility assays and genetic analyses, we determined that one of these candidates functioned as a het locus (het-e). The het-e locus has three divergent allelic groups that showed signatures of positive selection, intra- and intergroup recombination, and trans-species polymorphism. Our findings represent a compelling case of balancing selection functioning on multiple alleles across multiple loci potentially involved in Allorecognition.
Gad Shaulsky - One of the best experts on this subject based on the ideXlab platform.
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cellular Allorecognition and its roles in dictyostelium development and social evolution
The International Journal of Developmental Biology, 2019Co-Authors: Peter Kundert, Gad ShaulskyAbstract:The social amoeba Dictyostelium discoideum is a tractable model organism to study cellular Allorecognition, which is the ability of a cell to distinguish itself and its genetically similar relatives from more distantly related organisms. Cellular Allorecognition is ubiquitous across the tree of life and affects many biological processes. Depending on the biological context, these versatile systems operate both within and between individual organisms, and both promote and constrain functional heterogeneity. Some of the most notable Allorecognition systems mediate neural self-avoidance in flies and adaptive immunity in vertebrates. D. discoideum’s Allorecognition system shares several structures and functions with other Allorecognition systems. Structurally, its key regulators reside at a single genomic locus that encodes two highly polymorphic proteins, a transmembrane ligand called TgrC1 and its receptor TgrB1. These proteins exhibit isoform-specific, heterophilic binding across cells. Functionally, this interaction determines the extent to which co-developing D. discoideum strains co-aggregate or segregate during the aggregation phase of multicellular development. The Allorecognition system thus affects both development and social evolution, as available evidence suggests that the threat of developmental cheating represents a primary selective force acting on it. Other significant characteristics that may inform the study of Allorecognition in general include that D. discoideum’s Allorecognition system is a continuous and inclusive trait, it is pleiotropic, and it is temporally regulated.
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the polymorphic proteins tgrb1 and tgrc1 function as a ligand receptor pair in dictyostelium Allorecognition
Journal of Cell Science, 2017Co-Authors: Shigenori Hirose, Gong Chen, Adam Kuspa, Gad ShaulskyAbstract:Allorecognition is a key factor in Dictyostelium development and sociality. It is mediated by two polymorphic transmembrane proteins, TgrB1 and TgrC1, that contain extracellular immunoglobulin domains. TgrB1 and TgrC1 are necessary and sufficient for Allorecognition and they carry out separate albeit overlapping functions in development, but their mechanism of action is unknown. Here we show that TgrB1 acts as a receptor and TgrC1 as its ligand in cooperative aggregation and differentiation. The proteins bind each other in a sequence-specific manner, TgrB1 exhibits a cell-autonomous function, and TgrC1 acts non-cell-autonomously. The TgrB1 cytoplasmic tail is essential for its function and it becomes phosphorylated upon association with TgrC1. Dominant mutations in TgrB1 activate the receptor function and confer partial ligand independence. These roles in development and sociality suggests that Allorecognition is critical in the integration of individual cells into a coherent organism.
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altered n glycosylation modulates tgrb1 and tgrc1 mediated development but not Allorecognition in dictyostelium
Journal of Cell Science, 2015Co-Authors: Chenglin Frank Li, Gong Chen, Amanda Nicole Webb, Gad ShaulskyAbstract:ABSTRACT Cell surface adhesion receptors play diverse functions in multicellular development. In Dictyostelium , two immunoglobulin-like adhesion proteins, TgrB1 and TgrC1, are essential components with dual roles in morphogenesis and Allorecognition during development. TgrB1 and TgrC1 form a heterophilic adhesion complex during cell contact and mediate intercellular communication. The underlying signaling pathways, however, have not been characterized. Here, we report on a mutation that suppresses the tgrB–tgrC1 -defective developmental arrest. The mutated gene alg9 encodes a putative mannosyl transferase that participates in N- linked protein glycosylation. We show that alteration in N- linked glycosylation, caused by an alg9 mutation with a plasmid insertion ( alg9 ins ) or tunicamycin treatment, can partially suppress the developmental phenotypes caused by tgrC1 deletion or replacement with an incompatible allele. The alg9 ins mutation also preferentially primed cells toward a stalk-cell fate. Despite its effect on development, we found that altered N- linked glycosylation had no discernable effect on TgrB1-TgrC1-mediated Allorecognition. Our results show that N- linked protein glycosylation can modulate developmental processes without disturbing cell-cell recognition, suggesting that tgrB1 and tgrC1 have distinct effects in the two processes.
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Allorecognition via tgrb1 and tgrc1 mediates the transition from unicellularity to multicellularity in the social amoeba dictyostelium discoideum
Development, 2015Co-Authors: Shigenori Hirose, Gad Shaulsky, Balaji Santhanam, Mariko Katohkurosawa, Adam KuspaAbstract:The social amoeba Dictyostelium discoideum integrates into a multicellular organism when individual starving cells aggregate and form a mound. The cells then integrate into defined tissues and develop into a fruiting body that consists of a stalk and spores. Aggregation is initially orchestrated by waves of extracellular cyclic adenosine monophosphate (cAMP), and previous theory suggested that cAMP and other field-wide diffusible signals mediate tissue integration and terminal differentiation as well. Cooperation between cells depends on an Allorecognition system comprising the polymorphic adhesion proteins TgrB1 and TgrC1. Binding between compatible TgrB1 and TgrC1 variants ensures that non-matching cells segregate into distinct aggregates prior to terminal development. Here, we have embedded a small number of cells with incompatible allotypes within fields of developing cells with compatible allotypes. We found that compatibility of the allotype encoded by the tgrB1 and tgrC1 genes is required for tissue integration, as manifested in cell polarization, coordinated movement and differentiation into prestalk and prespore cells. Our results show that the molecules that mediate Allorecognition in D. discoideum also control the integration of individual cells into a unified developing organism, and this acts as a gating step for multicellularity.
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tgrc1 has distinct functions in dictyostelium development and Allorecognition
PLOS ONE, 2015Co-Authors: Yue Wang, Gad ShaulskyAbstract:The cell adhesion glycoproteins, TgrB1 and TgrC1, are essential for Dictyostelium development and Allorecognition, but it has been impossible to determine whether their pleiotropic roles are due to one common function or to distinct functions in separate pathways. Mutations in the respective genes, tgrB1 and tgrC1, abrogate both development and Allorecognition and the defects cannot be suppressed by activation of the cyclic AMP dependent protein kinase PKA, a central regulator of Dictyostelium development. Here we report that mutations in genes outside the known PKA pathway partially suppress the tgrC1-null developmental defect. We separated the pleiotropic roles of tgrC1 by testing the effects of a suppression mutation, stcinsA under different conditions. stcAins modified only the developmental defect of tgrC1– but not the Allorecognition defect, suggesting that the two functions are separable. The suppressor mutant phenotype also revealed that tgrC1 regulates stalk differentiation in a cell-autonomous manner and spore differentiation in a non-cell-autonomous manner. Moreover, stcAins did not modify the developmental defect of tgrB1–, but the less robust phenotype of tgrB1– obscures the possible role of stcA relative to tgrB1.
Jens Heller - One of the best experts on this subject based on the ideXlab platform.
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programmed cell death in neurospora crassa is controlled by the Allorecognition determinant rcd 1
Genetics, 2019Co-Authors: Asen Daskalov, Pierre Gladieux, Louise N Glass, Jens HellerAbstract:Nonself recognition following cell fusion between genetically distinct individuals of the same species in filamentous fungi often results in a programmed cell death (PCD) reaction, where the heterokaryotic fusion cell is compartmentalized and rapidly killed. The Allorecognition process plays a key role as a defense mechanism that restricts genome exploitation, resource plundering, and the spread of deleterious senescence plasmids and mycoviruses. Although a number of incompatibility systems have been described that function in mature hyphae, less is known about the PCD pathways in asexual spores, which represent the main infectious unit in various human and plant fungal pathogens. Here, we report the identification of regulator of cell death-1 (rcd-1), a novel Allorecognition gene, controlling PCD in germinating asexual spores of Neurospora crassa; rcd-1 is one of the most polymorphic genes in the genomes of wild N. crassa isolates. The coexpression of two antagonistic rcd-1-1 and rcd-1-2 alleles was necessary and sufficient to trigger cell death in fused germlings and in hyphae. Based on analysis of wild populations of N. crassa and N. discreta, rcd-1 alleles appeared to be under balancing selection and associated with trans-species polymorphisms. We shed light on genomic rearrangements that could have led to the emergence of the incompatibility system in Neurospora and show that rcd-1 belongs to a much larger gene family in fungi. Overall, our work contributes toward a better understanding of Allorecognition and PCD in an underexplored developmental stage of filamentous fungi.
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nlr surveillance of essential sec 9 snare proteins induces programmed cell death upon Allorecognition in filamentous fungi
Proceedings of the National Academy of Sciences of the United States of America, 2018Co-Authors: Pierre Gladieux, Louise N Glass, Jens Heller, Corinne Clave, Sven J SaupeAbstract:In plants and metazoans, intracellular receptors that belong to the NOD-like receptor (NLR) family are major contributors to innate immunity. Filamentous fungal genomes contain large repertoires of genes encoding for proteins with similar architecture to plant and animal NLRs with mostly unknown function. Here, we identify and molecularly characterize patatin-like phospholipase-1 (PLP-1), an NLR-like protein containing an N-terminal patatin-like phospholipase domain, a nucleotide-binding domain (NBD), and a C-terminal tetratricopeptide repeat (TPR) domain. PLP-1 guards the essential SNARE protein SEC-9; genetic differences at plp-1 and sec-9 function to trigger Allorecognition and cell death in two distantly related fungal species, Neurospora crassa and Podospora anserina Analyses of Neurospora population samples revealed that plp-1 and sec-9 alleles are highly polymorphic, segregate into discrete haplotypes, and show transspecies polymorphism. Upon fusion between cells bearing incompatible sec-9 and plp-1 alleles, Allorecognition and cell death are induced, which are dependent upon physical interaction between SEC-9 and PLP-1. The central NBD and patatin-like phospholipase activity of PLP-1 are essential for Allorecognition and cell death, while the TPR domain and the polymorphic SNARE domain of SEC-9 function in conferring allelic specificity. Our data indicate that fungal NLR-like proteins function similar to NLR immune receptors in plants and animals, showing that NLRs are major contributors to innate immunity in plants and animals and for Allorecognition in fungi.
Mohamed H Sayegh - One of the best experts on this subject based on the ideXlab platform.
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indirect Allorecognition of donor class i and ii major histocompatibility complex peptides promotes the development of transplant vasculopathy
Journal of The American Society of Nephrology, 2001Co-Authors: Karl L Womer, James R Stone, B Murphy, Anil Chandraker, Mohamed H SayeghAbstract:Abstract . Recent clinical and experimental evidence suggests that indirect Allorecognition may promote the development of chronic rejection, but definitive experimental studies are lacking. To study the contribution of indirect Allorecognition to chronic rejection, naive Lewis (RT1 1 ) rats were immunized with synthetic Wistar Furth (WF) class II-RT1 u .D (HLA-DR—like) or -RT1 u .B (HLA-DQ—like) or class I-RT1 u .A (HLA-A—like) peptides emulsified in complete Freund9s adjuvant 7 d before transplantation ( n = 5 to 7/group). Experimental and control animals then acted as recipients of fully mismatched WF vascularized cardiac allografts. Recipients received immunosuppression in the form of cyclosporine at a tapering dose that allows for long-term allograft survival. Animals were sacrificed at either 3 or 6 mo, with allograft arterial luminal occlusion scored on elastin stains by a blinded observer. At 3 mo, mean vessel scores were significantly higher in the RT1 u .A-immunized versus class II—immunized and control groups ( P u .A- and RT1 u .D-immunized versus RT1 u .B and control groups ( P In vitro studies show evidence of shifting MHC allopeptide immunogenicity. It was concluded that T cells primed by specific donor class I and II MHC allopeptides promote the development of chronic vascularized allograft rejection. These novel observations provide definitive evidence of a link between indirect Allorecognition and the development and progression of chronic rejection.
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indirect Allorecognition of mismatched donor hla class ii peptides in lung transplant recipients with bronchiolitis obliterans syndrome
American Journal of Transplantation, 2001Co-Authors: Scott I Reznik, Mohamed H Sayegh, Karl L Womer, Andres Jaramillo, Krovvidi S R Sivasai, Elbert P Trulock, Alexander G Patterson, T MohanakumarAbstract:A correlation between indirect Allorecognition of mismatched donor HLA class I peptides and development of bronchiolitis obliterans syndrome (BOS) after lung transplantation has been previously observed. The aim of this study was to determine whether there was a correlation between indirect Allorecognition of mismatched donor HLA class II peptides and development of BOS after lung transplantation. Peripheral blood mononuclear cells from nine BOS„ and nine BOS‐ lung transplant recipients were cultured with synthetic peptides corresponding to the b-chain hypervariable region of a mismatched donor HLA-DR molecule. Then, proliferative alloreactivity as well as frequency of alloreactive T cells were determined. In addition, the immunodominant epitopes from the donor HLA-DR molecules were identified in selected patients. T cells from BOS„ patients showed a dose-dependent proliferative alloreactivity against donor HLA-DR peptides that was significantly higher than that observed in BOS‐ patients (p‰0.001). Similarly, the frequency of HLA-DR alloreactive T cells was significantly higher in BOS„ patients than in BOS‐ patients (p‰0.001). This T-cell alloreactivity was directed against a single immunodominant HLA-DR peptide. These results suggest that indirect alloreactivity to donor HLA class II molecules may play a role in the pathogenesis of BOS after lung transplantation.
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involvement of the direct and indirect pathways of Allorecognition in tolerance induction
Philosophical Transactions of the Royal Society B, 2001Co-Authors: Karl L Womer, Mohamed H Sayegh, Hugh AuchinclossAbstract:It is generally accepted that there are two pathways of Allorecognition, direct and indirect, that together contribute to allograft rejection. Although it has been suggested that the direct pathway predominates during early acute rejection and that the indirect pathway provides a continuous supply of alloantigen responsible for chronic rejection, the true relative contribution of each pathway to the overall rejection process is still not entirely known. It is clear, however, that any strategies designed to achieve the ultimate goal in transplantation, the induction of tolerance, will need to take into account both pathways. This review seeks to explore the involvement of the direct and indirect pathways of Allorecognition on a mechanistic level as it relates to the induction of tolerance. A brief historical perspective is included for each pathway as well as a comprehensive review of the mechanisms felt to be active during tolerance induction.
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indirect Allorecognition of major histocompatibility complex allopeptides in human renal transplant recipients with chronic graft dysfunction
Transplantation, 1997Co-Authors: John P Vella, C B Carpenter, Monica Spadaforaferreira, Barbara Murphy, Stephen I Alexander, William E Harmon, Mohamed H SayeghAbstract:Background. It has been suggested that T cells primed by processed donor major histocompatibility complex antigen (the indirect pathway of Allorecognition) may be responsible for mediating chronic allograft rejection. The purpose of this study was to develop a clinically useful assay to study the occurrence of indirect Allorecognition during chronic rejection in humans. Methods. A panel of 20 mer peptides corresponding to the hypervariable regions of HLA-DRB1 * 0101, DRB1 * 1501, and DRB1 * 0301 were synthesized. Lymphocytes obtained from renal allograft recipients were cocultured with these peptides. Proliferation was assayed by DNA incorporation of [ 3 H]thymidine, and positive proliferation was defined by a statistically significant increase in counts per minute over background with a minimum stimulation index of 2. The precursor frequency of allopeptide reactive T cells was determined by limiting dilution analysis. Results. Lymphocytes from 82% of patients who were mismatched for at least one of the three DR molecules and had chronic allograft dysfunction specifically proliferated to the mismatched allopeptides (n=11). Proliferation was seen in only 6% of control subjects (2/33, P<0.0001). The proliferative response was low grade and was best detected on day 7-8 of culture in vitro. The precursor frequency of peptide-specific T cells was more than 10-fold higher compared with controls (P<0.001). Conclusions. These data demonstrate for the first time that T cells of patients with chronic graft dysfunction are primed to recognize and respond to specific donor-derived major histocompatibility complex allopeptides. Our results support the hypothesis that T cells primed via the indirect pathway of Allorecognition may be important mediators of chronic rejection and provide the rationale to develop specific therapeutic strategies to prevent or interrupt this process.
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role of indirect Allorecognition in allograft rejection
International Reviews of Immunology, 1996Co-Authors: Mohamed H Sayegh, C B CarpenterAbstract:: It is now clear from animal studies that indirect Allorecognition occurs during allograft rejection and that this pathway plays a role in mediating the rejection process. Whether this pathway is the dominant pathway responsible for chronic rejection remains to be established, but this is an intriguing hypothesis that may have major implications for development of novel therapies for this disorder. In addition, there are data to indicate that indirect Allorecognition may play a role in maintenance of allograft acceptance, and that provision of appropriate MHC peptides via different routes can result in potent degrees of specific allo-tolerance. Expanded experimentation in animals and in humans is therefore in order; first, to dissect more closely the molecular basis of Allorecognition and establish the role of the indirect pathway in acute versus chronic rejection, and second to utilize the immunomodulatory properties of MHC peptides or other novel strategies which targets indirect Allorecognition in promoting graft acceptance.
