Allograft rejection (Homo sapiens)

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1-6ATTACKENDOTHELIALCELLSTT: Therapeutic Target (increase)peroxisomeC5 CONVERTASENEUTROPHILS/MACRO/NKMEMBRANE ATTACK COMPLEX ACTIVATIONApoptosisC1 COMPLEXTT: Therapeutic Target (decrease)IgM?Donor CellsTregMacrophageC3 CONVERTASEnucleusCHRONIC AMR REJECTIONIgGAbs toLegendFibrosisALTERNATIVE COMPLEMENTPATHWAYY-CVFPlasmacellCLASSICAL COMPLEMENTPATHWAYACUTE AMR REJECTIONCD 8+ T cellDonor CellMaturationTH2cellTH17Naive T cellTTTH1cellDirectDirect Donor APCIndirectRecipient APCC3COL5CCL19VIMHARSCCL21BHMT2C5PDGFRALRRK2GNLYIFNGCXCL9IL21AGTR1HARSC5CXCL9CSNK2A2GABPABHMT2CXCL11CXCL9GDNFPDGFRAMICAGDNFCXCL11PECRCCL19IL8CSNK2A2IL1AC4AC3IL21TUBA1BCXCL11CCL21IFNGIL2GDNFCD28IFNGIL13IL4IL12BHLA-Bko:K10785Nitric oxideIL10Cell adhesion molecules (CAMs)HLA-GHLA-FPRF1HLA-CIL2IL21FOXP3IL22HLA-EGZMBTGFB1IL10TNFko:K10784IL5IL17AIL4IL12AIFNGIL5CD 4+ T cellIndirectCD40LGB cellCD40CD 8+ T cellFASHLA-AFASLGBOLA class I histocompatibility antigenko:K06856Allograft RejectionBelataceptCTLA4C2C9C8bC6Daf1C1qaC1qbC4aC7C8aC4bC1qcTTC3Daf1ECULIZUMABCD40LGCD40CD 8+ T cellCD 8+ T cellCD 8+ T cellTH1cellCD 8+ T cellCD 8+ T cellCD 8+ T cellNaive T cellNaive T cellNaive T cellTH1cellTH1cellCD 4+ T cellCD 4+ T cellCD 4+ T cellTregTregTregTH17TH17TH17PlasmacellPlasmacellPlasmacellB cellB cellB cellTH2cellTH2cellCASP8CASP7CASP3CASP9TH2cellHLAIgG3IgG1NONHLAAntibodiesPRKCZTacrolimusCiclosporinDaclizumabBasiliximabPrednisoneMethylprednisoloneSirolimusIL2RAIL1BDonor ParenchymalGraft CellsMHCIMHCIIHLA-DRB3HLA-DRAHLA-DMBHLA-DRB1HLA-DQA2HLA-DPA1HLA-DOBHLA-DRB4HLA-DOAHLA-DQA1HLA-DQB1HLA-DRB5CD80HLA-DMAHLA-DPB1MHCIICD28TCRTCRDirect Donor APCCD80HLA-EHLA-GHLA-FHLA-BHLA-CHLA-ACD86MHCIMHCIITTTTTTGZMBPRF1TTTTTTFenofibrate7FenofibrateTT7TTTTTT


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.

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Bibliography

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  1. Heeger PS, Dinavahi R; ''Transplant immunology for non-immunologist.''; Mt Sinai J Med, 2012 PubMed Europe PMC Scholia
  2. 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 Europe PMC Scholia
  3. Stegall MD, Chedid MF, Cornell LD; ''The role of complement in antibody-mediated rejection in kidney transplantation.''; Nat Rev Nephrol, 2012 PubMed Europe PMC Scholia
  4. Dragun D, Philippe A, Catar R; ''Role of non-HLA antibodies in organ transplantation.''; Curr Opin Organ Transplant, 2012 PubMed Europe PMC Scholia
  5. 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 Europe PMC Scholia
  6. 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 Europe PMC Scholia
  7. Nankivell BJ, Alexander SI; ''Rejection of the kidney allograft.''; N Engl J Med, 2010 PubMed Europe PMC Scholia
  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 Europe PMC Scholia
  9. 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 Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
120805view08:58, 11 January 2022SusanOntology Term : 'adaptive immune response pathway' added !
120776view21:41, 4 January 2022EweitzModified title
106557view00:35, 6 September 2019KhanspersModified description
105876view04:50, 16 August 2019KhanspersModified description
105523view05:58, 9 August 2019KhanspersModified description
103048view09:07, 7 February 2019DeSlRemoved "last modified" item
103047view09:06, 7 February 2019DeSlChanged kegg orthologs to mapping Ids
97563view07:32, 25 May 2018Fehrhartfixed lines
92211view21:02, 9 May 2017AlexanderPicoFixed a few more xrefs
92210view20:57, 9 May 2017AlexanderPicoFixed complement protein xrefs: updated from mouse to human identifiers
90020view19:29, 8 October 2016AlexanderPicoModified description
89949view14:15, 6 October 2016MkutmonModified description
88895view07:38, 17 August 2016MirellaKalafatiOntology Term : 'disease pathway' added !
84648view22:09, 10 March 2016KhanspersReverted to version '10:31, 7 January 2015' by Khanspers
84647view22:08, 10 March 2016KhanspersQuick edit to datanode annotation or property
78554view10:31, 7 January 2015MaintBotadded missing graphIds
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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External references

DataNodes

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

Annotated Interactions

No annotated interactions

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