Allograft Rejection (Homo sapiens)

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Curation Tags

Description

This pathway illustrates molecular interactions involved in the fundamental adaptive immune response for allograft destruction. This pathway was adapted in large part from the KEGG pathway http://www.genome.jp/kegg/pathway/hsa/hsa05330.html. In the initial step of this diagram, antigen presenting cells (APC’s), either those from the donor (direct pathway) or from the recipient (indirect pathway) activate naive t cells leading to both CD8+ and CD4+ T cell maturation. CD8+ stimulated T cells lead to apoptosis of the allograft donor cells whereas CD4+ T cells differentiate into TH1, TH2, T17, and Treg cells. Activated TH1 produces TNFA and NO and damages donor graft cells by cytotoxicity. TH2 cell activates B cells. Activated B cells lead to plasma cell formation followed by IgG antibodies and the complement cascade pathway in acute antibody-mediated rejection (AMR) and chronic AMR with C3 being the therapeutic target. Exogenous treatment with YCF inhibits C3, thus preventing AMR. Eculizumab binds to C5 which prevent C5a production and the membrane attack complex. C3a and C35 act as potent chemotactic factors, promoting the infiltration of pro-inflammatory cells. Belatacept inhibits CD80/86 binding to CD28. Corticosteroids inhibit pro-inflammatory cytokines. Corticosteroids contribute to immune suppression such as CTLA4 which inhibits T-cell activation.

Ontology Tags

 

Bibliography

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  1. Dragun D, Philippe A, Catar R; ''Role of non-HLA antibodies in organ transplantation.''; Curr Opin Organ Transplant, 2012 PubMed
  2. Naesens M, Lerut E, Sarwal M, Van Damme B, Vanrenterghem Y, Kuypers DR; ''Balancing efficacy and toxicity of kidney transplant immunosuppression.''; Transplant Proc, 2009 PubMed
  3. Satterwhite T, Chua MS, Hsieh SC, Chang S, Scandling J, Salvatierra O, Sarwal MM; ''Increased expression of cytotoxic effector molecules: different interpretations for steroid-based and steroid-free immunosuppression.''; Pediatr Transplant, 2003 PubMed
  4. Heeger PS, Dinavahi R; ''Transplant immunology for non-immunologist.''; Mt Sinai J Med, 2012 PubMed
  5. Stegall MD, Chedid MF, Cornell LD; ''The role of complement in antibody-mediated rejection in kidney transplantation.''; Nat Rev Nephrol, 2012 PubMed
  6. Sigdel TK, Li L, Tran TQ, Khatri P, Naesens M, Sansanwal P, Dai H, Hsieh SC, Sarwal MM; ''Non-HLA antibodies to immunogenic epitopes predict the evolution of chronic renal allograft injury.''; J Am Soc Nephrol, 2012 PubMed
  7. Zarkhin V, Kambham N, Li L, Kwok S, Hsieh SC, Salvatierra O, Sarwal MM; ''Characterization of intra-graft B cells during renal allograft rejection.''; Kidney Int, 2008 PubMed
  8. Roedder S, Kimura N, Okamura H, Hsieh SC, Gong Y, Sarwal MM; ''Significance and suppression of redundant IL17 responses in acute allograft rejection by bioinformatics based drug repositioning of fenofibrate.''; PLoS One, 2013 PubMed
  9. Nankivell BJ, Alexander SI; ''Rejection of the kidney allograft.''; N Engl J Med, 2010 PubMed

History

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CompareRevisionActionTimeUserComment
76328view08:09, 2 July 2014MkutmonChanged database annotations from "Ensembl Human" to "Ensembl"
74457view22:34, 22 April 2014Khanspersreplaced arcs with curved interactions
71614view19:32, 17 October 2013DMicaelSpecify description
71278view22:58, 16 October 2013MaintBotUpdated UniProt/TrEMBL data source
71219view21:03, 14 October 2013DMicaelSpecify description
71218view20:53, 14 October 2013DMicaelSpecify description
71214view20:14, 14 October 2013DMicaelSpecify description
71213view19:32, 14 October 2013DMicaelPeriodical save, work in progress
71212view19:03, 14 October 2013DMicaelSpecify description
71068view21:49, 1 October 2013DMicaelmodified pathway
71067view21:34, 1 October 2013DMicaelpathway clarification
71066view21:30, 1 October 2013DMicaelPeriodical save, work in progress
67948view11:14, 28 June 2013DdiglesOntology Term : 'allograft rejection pathway' added !
63152view20:17, 8 May 2013MaintBotUpdating GPML version
60628view16:17, 24 March 2013NsalomonisModified description
60386view18:14, 18 March 2013DMicaelModified title
60383view16:56, 18 March 2013DMicaelModified description
60282view00:14, 16 March 2013NsalomonisSpecify description
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60279view23:57, 15 March 2013NsalomonisPeriodical save, work in progress
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External references

View all...
NameTypeDatabase referenceComment
HLA-AGeneProduct3105 (Entrez Gene) Original kegg element: gene;32;hsa:3105 hsa:3106 hsa:3107 hsa:3133 hsa:3134 hsa:3135 hsa:652614
IL1BGeneProductENSG00000125538 (Ensembl)
CXCL11GeneProductENSG00000169248 (Ensembl)
C4bGeneProduct12268 (Entrez Gene)
CCL21GeneProductENSG00000137077 (Ensembl)
CD86GeneProduct942 (Entrez Gene) Original kegg element: gene;35;hsa:941 hsa:942
IL21GeneProductENSG00000138684 (Ensembl)
C8bGeneProduct110382 (Entrez Gene)
GDNFGeneProductENSG00000168621 (Ensembl)
TacrolimusMetabolite104987-11-3 (CAS)
IFNGGeneProductENSG00000111537 (Ensembl)
HLA-DRB4GeneProduct3126 (Entrez Gene) Original kegg element: gene;10;hsa:100133583 hsa:3108 hsa:3109 hsa:3111 hsa:3112 hsa:3113 hsa:3115 hsa:3117 hsa:3118 hsa:3119 hsa:3122 hsa:3123 hsa:3125 hsa:3126 hsa:3127
CSNK2A2GeneProductENSG00000070770 (Ensembl)
IL5GeneProductENSG00000113525 (Ensembl)
PDGFRAGeneProductENSG00000134853 (Ensembl)
BelataceptMetabolite706808-37-9 (CAS)
BHMT2GeneProductENSG00000132840 (Ensembl)
C1qbGeneProduct12260 (Entrez Gene)
CCL19GeneProductENSG00000172724 (Ensembl)
CASP7GeneProductENSG00000165806 (Ensembl)
HARSGeneProductENSG00000170445 (Ensembl)
PrednisoneMetabolite53-03-2 (CAS)
C3GeneProductENSG00000125730 (Ensembl)
HLA-DRB1GeneProduct3123 (Entrez Gene) Original kegg element: gene;10;hsa:100133583 hsa:3108 hsa:3109 hsa:3111 hsa:3112 hsa:3113 hsa:3115 hsa:3117 hsa:3118 hsa:3119 hsa:3122 hsa:3123 hsa:3125 hsa:3126 hsa:3127
C5GeneProductENSG00000106804 (Ensembl)
HLA-DRB5GeneProduct3127 (Entrez Gene) Original kegg element: gene;10;hsa:100133583 hsa:3108 hsa:3109 hsa:3111 hsa:3112 hsa:3113 hsa:3115 hsa:3117 hsa:3118 hsa:3119 hsa:3122 hsa:3123 hsa:3125 hsa:3126 hsa:3127
C4AGeneProduct720 (Entrez Gene)
CXCL9GeneProductENSG00000138755 (Ensembl)
MICAGeneProduct100507436 (Entrez Gene)
CD40GeneProduct958 (Entrez Gene) Original kegg element: gene;37;hsa:958
AGTR1GeneProductENSG00000144891 (Ensembl)
BOLA class I histocompatibility antigenGeneProduct652614 (Entrez Gene) Original kegg element: gene;20;hsa:3105 hsa:3106 hsa:3107 hsa:3133 hsa:3134 hsa:3135 hsa:652614
COL5GeneProductENSG00000130635 (Ensembl)
C2GeneProduct12263 (Entrez Gene)
TUBA1BGeneProductENSG00000123416 (Ensembl)
Daf1GeneProduct13136 (Entrez Gene)
PECRGeneProductENSG00000115425 (Ensembl)
C7GeneProduct109828 (Entrez Gene)
VIMGeneProductENSG00000026025 (Ensembl)
ECULIZUMABMetabolite219685-50-4 (CAS)
GABPAGeneProductENSG00000154727 (Ensembl)
CASP9GeneProductENSG00000132906 (Ensembl)
IL8GeneProductENSG00000169429 (Ensembl)
DaclizumabMetabolite152923-56-3 (CAS)
LRRK2GeneProductENSG00000188906 (Ensembl)
SirolimusMetabolite53123-88-9 (CAS)
IL2GeneProductENSG00000109471 (Ensembl)
HLA-DRAGeneProduct3122 (Entrez Gene) Original kegg element: gene;10;hsa:100133583 hsa:3108 hsa:3109 hsa:3111 hsa:3112 hsa:3113 hsa:3115 hsa:3117 hsa:3118 hsa:3119 hsa:3122 hsa:3123 hsa:3125 hsa:3126 hsa:3127
IL1AGeneProductENSG00000115008 (Ensembl)
HLA-DPA1GeneProduct3113 (Entrez Gene) Original kegg element: gene;10;hsa:100133583 hsa:3108 hsa:3109 hsa:3111 hsa:3112 hsa:3113 hsa:3115 hsa:3117 hsa:3118 hsa:3119 hsa:3122 hsa:3123 hsa:3125 hsa:3126 hsa:3127
GNLYGeneProductENSG00000115523 (Ensembl)
HLA-DQA1GeneProduct3117 (Entrez Gene) Original kegg element: gene;10;hsa:100133583 hsa:3108 hsa:3109 hsa:3111 hsa:3112 hsa:3113 hsa:3115 hsa:3117 hsa:3118 hsa:3119 hsa:3122 hsa:3123 hsa:3125 hsa:3126 hsa:3127
ABCB1GeneProductENSG00000085563 (Ensembl)
HLA-DMAGeneProduct3108 (Entrez Gene) Original kegg element: gene;10;hsa:100133583 hsa:3108 hsa:3109 hsa:3111 hsa:3112 hsa:3113 hsa:3115 hsa:3117 hsa:3118 hsa:3119 hsa:3122 hsa:3123 hsa:3125 hsa:3126 hsa:3127
CXCL12GeneProductENSG00000107562 (Ensembl)
PRF1GeneProductENSG00000180644 (Ensembl)
STAT1GeneProductENSG00000115415 (Ensembl)
IFNGGeneProduct3458 (Entrez Gene) Original kegg element: gene;34;hsa:3458
VEGFAGeneProductENSG00000112715 (Ensembl)
CD40LGGeneProduct959 (Entrez Gene) Original kegg element: gene;38;hsa:959
CXCL13GeneProductENSG00000156234 (Ensembl)
FASGeneProduct355 (Entrez Gene) Original kegg element: gene;17;hsa:355
CXCR5GeneProductENSG00000160683 (Ensembl)
FASLGGeneProduct356 (Entrez Gene) Original kegg element: gene;18;hsa:356
CD28GeneProduct940 (Entrez Gene) Original kegg element: gene;36;hsa:940
ko:K06856GeneProductK06856 (Kegg ortholog)
IL13GeneProductENSG00000169194 (Ensembl)
CTLA4GeneProductENSG00000163599 (Ensembl)
IL4GeneProductENSG00000113520 (Ensembl)
C9GeneProduct12279 (Entrez Gene)
IL12BGeneProduct3593 (Entrez Gene) Original kegg element: gene;41;hsa:3592 hsa:3593
C6GeneProduct12274 (Entrez Gene)
HLA-BGeneProduct3106 (Entrez Gene) Original kegg element: gene;32;hsa:3105 hsa:3106 hsa:3107 hsa:3133 hsa:3134 hsa:3135 hsa:652614
C1qaGeneProduct12259 (Entrez Gene) update: C1QA HUMAN
ko:K10785GeneProductK10784... (Kegg ortholog)
C4aGeneProduct625018 (Entrez Gene)
Nitric oxideMetaboliteC00533 (KEGG Compound)
C8aGeneProduct230558 (Entrez Gene)
IL10GeneProduct3586 (Entrez Gene) Original kegg element: gene;31;hsa:3586
C1qcGeneProduct12262 (Entrez Gene) update C1QC HUMAN
Cell adhesion molecules (CAMs)GeneProductpath:hsa04514 (KEGG Genes) Original kegg element: map;7;path:hsa04514
CASP8GeneProductENSG00000064012 (Ensembl)
HLA-GGeneProduct3135 (Entrez Gene) Original kegg element: gene;32;hsa:3105 hsa:3106 hsa:3107 hsa:3133 hsa:3134 hsa:3135 hsa:652614
CASP3GeneProductENSG00000164305 (Ensembl)
HLA-FGeneProduct3134 (Entrez Gene) Original kegg element: gene;32;hsa:3105 hsa:3106 hsa:3107 hsa:3133 hsa:3134 hsa:3135 hsa:652614
PRKCZGeneProductENSG00000067606 (Ensembl)
PRF1GeneProduct5551 (Entrez Gene) Original kegg element: gene;22;hsa:5551
CiclosporinMetabolite59865-13-3 (CAS)
HLA-CGeneProduct3107 (Entrez Gene) Original kegg element: gene;32;hsa:3105 hsa:3106 hsa:3107 hsa:3133 hsa:3134 hsa:3135 hsa:652614
BasiliximabMetabolite152923-56-3 (CAS)
FOXP3GeneProductENSG00000049768 (Ensembl)
MethylprednisoloneMetabolite83-43-2 (CAS)
IL22GeneProductENSG00000127318 (Ensembl)
IL2RAGeneProductENSG00000134460 (Ensembl)
HLA-EGeneProduct3133 (Entrez Gene) Original kegg element: gene;32;hsa:3105 hsa:3106 hsa:3107 hsa:3133 hsa:3134 hsa:3135 hsa:652614
HLA-DRB3GeneProduct3125 (Entrez Gene) Original kegg element: gene;10;hsa:100133583 hsa:3108 hsa:3109 hsa:3111 hsa:3112 hsa:3113 hsa:3115 hsa:3117 hsa:3118 hsa:3119 hsa:3122 hsa:3123 hsa:3125 hsa:3126 hsa:3127
GZMBGeneProduct3002 (Entrez Gene) Original kegg element: gene;21;hsa:3002
HLA-DMBGeneProduct3109 (Entrez Gene) Original kegg element: gene;10;hsa:100133583 hsa:3108 hsa:3109 hsa:3111 hsa:3112 hsa:3113 hsa:3115 hsa:3117 hsa:3118 hsa:3119 hsa:3122 hsa:3123 hsa:3125 hsa:3126 hsa:3127
TGFB1GeneProductENSG00000105329 (Ensembl)
HLA-DQA2GeneProduct3118 (Entrez Gene) Original kegg element: gene;10;hsa:100133583 hsa:3108 hsa:3109 hsa:3111 hsa:3112 hsa:3113 hsa:3115 hsa:3117 hsa:3118 hsa:3119 hsa:3122 hsa:3123 hsa:3125 hsa:3126 hsa:3127
IL10GeneProductENSG00000136634 (Ensembl)
HLA-DOBGeneProduct3112 (Entrez Gene) Original kegg element: gene;10;hsa:100133583 hsa:3108 hsa:3109 hsa:3111 hsa:3112 hsa:3113 hsa:3115 hsa:3117 hsa:3118 hsa:3119 hsa:3122 hsa:3123 hsa:3125 hsa:3126 hsa:3127
TNFGeneProduct7124 (Entrez Gene) Original kegg element: gene;39;hsa:7124
HLA-DOAGeneProduct3111 (Entrez Gene) Original kegg element: gene;10;hsa:100133583 hsa:3108 hsa:3109 hsa:3111 hsa:3112 hsa:3113 hsa:3115 hsa:3117 hsa:3118 hsa:3119 hsa:3122 hsa:3123 hsa:3125 hsa:3126 hsa:3127
ko:K10784GeneProductK10784... (Kegg ortholog)
HLA-DQB1GeneProduct3119 (Entrez Gene) Original kegg element: gene;10;hsa:100133583 hsa:3108 hsa:3109 hsa:3111 hsa:3112 hsa:3113 hsa:3115 hsa:3117 hsa:3118 hsa:3119 hsa:3122 hsa:3123 hsa:3125 hsa:3126 hsa:3127
IL5GeneProduct3567 (Entrez Gene) Original kegg element: gene;27;hsa:3567
CD80GeneProduct941 (Entrez Gene) Original kegg element: gene;35;hsa:941 hsa:942
IL17AGeneProductENSG00000112115 (Ensembl)
HLA-DPB1GeneProduct3115 (Entrez Gene) Original kegg element: gene;10;hsa:100133583 hsa:3108 hsa:3109 hsa:3111 hsa:3112 hsa:3113 hsa:3115 hsa:3117 hsa:3118 hsa:3119 hsa:3122 hsa:3123 hsa:3125 hsa:3126 hsa:3127
IL4GeneProduct3565 (Entrez Gene) Original kegg element: gene;26;hsa:3565
GZMBGeneProductENSG00000100453 (Ensembl)
IL12AGeneProduct3592 (Entrez Gene) Original kegg element: gene;41;hsa:3592 hsa:3593
FenofibrateMetabolite49562-28-9 (CAS)
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