Allograft rejection (WP2328)

This pathway illustrates molecular interactions involved in the fundamental adaptive immune response for allograft destruction. This pathway was adapted in large part from [http://www.genome.jp/kegg/pathway/hsa/hsa05330.html KEGG]. 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. Proteins on this pathway have targeted assays available via the [https://assays.cancer.gov/available_assays?wp_id=WP2328 CPTAC Assay Portal]
last edited

Authors

Nsalomonis, MaintBot, DMicael, Ddigles, Khanspers, Mkutmon, MirellaKalafati, AlexanderPico, Fehrhart, DeSl, Eweitz, and Susan

Cited In

Organism

Homo sapiens

Communities

Annotations

Pathway Ontology: allograft rejection pathway disease pathway adaptive immune response pathway

Participants

Label Type Compact Identifier
GDNF GeneProduct ensembl:ENSG00000168621
C5 GeneProduct ensembl:ENSG00000106804
CCL19 GeneProduct ensembl:ENSG00000172724
VEGFA GeneProduct ensembl:ENSG00000112715
MICA GeneProduct ncbigene:100507436
BHMT2 GeneProduct ensembl:ENSG00000132840
LRRK2 GeneProduct ensembl:ENSG00000188906
PECR GeneProduct ensembl:ENSG00000115425
GDNF GeneProduct ensembl:ENSG00000168621
PDGFRA GeneProduct ensembl:ENSG00000134853
STAT1 GeneProduct ensembl:ENSG00000115415
IL21 GeneProduct ensembl:ENSG00000138684
C5 GeneProduct ensembl:ENSG00000106804
CXCL11 GeneProduct ensembl:ENSG00000169248
IL2 GeneProduct ensembl:ENSG00000109471
CXCR5 GeneProduct ensembl:ENSG00000160683
GNLY GeneProduct ensembl:ENSG00000115523
HARS GeneProduct ensembl:ENSG00000170445
BHMT2 GeneProduct ensembl:ENSG00000132840
CXCL9 GeneProduct ensembl:ENSG00000138755
CCL19 GeneProduct ensembl:ENSG00000172724
CXCL9 GeneProduct ensembl:ENSG00000138755
CXCL13 GeneProduct ensembl:ENSG00000156234
CSNK2A2 GeneProduct ensembl:ENSG00000070770
C3 GeneProduct ensembl:ENSG00000125730
TUBA1B GeneProduct ensembl:ENSG00000123416
PDGFRA GeneProduct ensembl:ENSG00000134853
GDNF GeneProduct ensembl:ENSG00000168621
CXCL12 GeneProduct ensembl:ENSG00000107562
CCL21 GeneProduct ensembl:ENSG00000137077
GABPA GeneProduct ensembl:ENSG00000154727
AGTR1 GeneProduct ensembl:ENSG00000144891
CXCL11 GeneProduct ensembl:ENSG00000169248
CSNK2A2 GeneProduct ensembl:ENSG00000070770
C3 GeneProduct ensembl:ENSG00000125730
CCL21 GeneProduct ensembl:ENSG00000137077
IL1A GeneProduct ensembl:ENSG00000115008
C4A GeneProduct ncbigene:720
COL5 GeneProduct ensembl:ENSG00000130635
IL8 GeneProduct ensembl:ENSG00000169429
HARS GeneProduct ensembl:ENSG00000170445
IFNG GeneProduct ensembl:ENSG00000111537
CXCL11 GeneProduct ensembl:ENSG00000169248
CXCL9 GeneProduct ensembl:ENSG00000138755
VIM GeneProduct ensembl:ENSG00000026025
IL21 GeneProduct ensembl:ENSG00000138684
IFNG GeneProduct ensembl:ENSG00000111537
ABCB1 GeneProduct ensembl:ENSG00000085563
CD28 GeneProduct ncbigene:940
IFNG GeneProduct ensembl:ENSG00000111537
IL13 GeneProduct ensembl:ENSG00000169194
IL4 GeneProduct ensembl:ENSG00000113520
IL12B GeneProduct ncbigene:3593
HLA-B GeneProduct ncbigene:3106
TRBV GeneProduct ncbigene:6957
T-cell receptor beta chain V region None
Nitric oxide Metabolite kegg.compound:C00533
IL10 GeneProduct ncbigene:3586
Cell adhesion molecules (CAMs) GeneProduct kegg.genes:path:hsa04514
HLA-G GeneProduct ncbigene:3135
HLA-F GeneProduct ncbigene:3134
PRF1 GeneProduct ncbigene:5551
HLA-C GeneProduct ncbigene:3107
IL2 GeneProduct ensembl:ENSG00000109471
IL21 GeneProduct ensembl:ENSG00000138684
FOXP3 GeneProduct ensembl:ENSG00000049768
IL22 GeneProduct ensembl:ENSG00000127318
HLA-E GeneProduct ncbigene:3133
GZMB GeneProduct ncbigene:3002
TGFB1 GeneProduct ensembl:ENSG00000105329
IL10 GeneProduct ensembl:ENSG00000136634
TNF GeneProduct ncbigene:7124
TRAV GeneProduct ncbigene:6955
IL5 GeneProduct ncbigene:3567
IL17A GeneProduct ensembl:ENSG00000112115
IL4 GeneProduct ncbigene:3565
IL12A GeneProduct ncbigene:3592
IFNG GeneProduct ncbigene:3458
IL5 GeneProduct ensembl:ENSG00000113525
CD40LG GeneProduct ncbigene:959
CD40 GeneProduct ncbigene:958
FAS GeneProduct ncbigene:355
HLA-A GeneProduct ncbigene:3105
FASLG GeneProduct ncbigene:356
BOLA class I histocompatibility antigen GeneProduct ncbigene:652614
immunoglobulin heavy chain GeneProduct ncbiprotein:XP_011544500
Belatacept Metabolite cas:706808-37-9
CTLA4 GeneProduct ensembl:ENSG00000163599
C2 GeneProduct ncbigene:717
C9 GeneProduct ncbigene:735
C8B GeneProduct ncbigene:732
C6 GeneProduct ncbigene:729
CD55 GeneProduct ncbigene:1604
C1QA GeneProduct ncbigene:712
C1QB GeneProduct ncbigene:713
C4A GeneProduct ncbigene:720
C7 GeneProduct ncbigene:730
C8A GeneProduct ncbigene:731
C4B GeneProduct ncbigene:721
C1QC GeneProduct ncbigene:714
C3 GeneProduct ensembl:ENSG00000125730
CD55 GeneProduct ncbigene:1604
ECULIZUMAB Metabolite cas:219685-50-4
CD40LG GeneProduct ncbigene:959
CD40 GeneProduct ncbigene:958
CASP8 GeneProduct ensembl:ENSG00000064012
CASP7 GeneProduct ensembl:ENSG00000165806
CASP3 GeneProduct ensembl:ENSG00000164305
CASP9 GeneProduct ensembl:ENSG00000132906
PRKCZ GeneProduct ensembl:ENSG00000067606
Tacrolimus Metabolite cas:104987-11-3
Ciclosporin Metabolite cas:59865-13-3
Daclizumab Metabolite cas:152923-56-3
Basiliximab Metabolite cas:152923-56-3
Prednisone Metabolite cas:53-03-2
Methylprednisolone Metabolite cas:83-43-2
Sirolimus Metabolite cas:53123-88-9
IL2RA GeneProduct ensembl:ENSG00000134460
IL1B GeneProduct ensembl:ENSG00000125538
HLA-DRB3 GeneProduct ncbigene:3125
HLA-DRA GeneProduct ncbigene:3122
HLA-DMB GeneProduct ncbigene:3109
HLA-DRB1 GeneProduct ncbigene:3123
HLA-DQA2 GeneProduct ncbigene:3118
HLA-DPA1 GeneProduct ncbigene:3113
HLA-DOB GeneProduct ncbigene:3112
HLA-DRB4 GeneProduct ncbigene:3126
HLA-DOA GeneProduct ncbigene:3111
HLA-DQA1 GeneProduct ncbigene:3117
HLA-DQB1 GeneProduct ncbigene:3119
HLA-DRB5 GeneProduct ncbigene:3127
CD80 GeneProduct ncbigene:941
HLA-DMA GeneProduct ncbigene:3108
HLA-DPB1 GeneProduct ncbigene:3115
CD28 GeneProduct ncbigene:940
CD80 GeneProduct ncbigene:941
HLA-E GeneProduct ncbigene:3133
HLA-G GeneProduct ncbigene:3135
HLA-F GeneProduct ncbigene:3134
HLA-B GeneProduct ncbigene:3106
HLA-C GeneProduct ncbigene:3107
HLA-A GeneProduct ncbigene:3105
CD86 GeneProduct ncbigene:942
GZMB GeneProduct ensembl:ENSG00000100453
PRF1 GeneProduct ensembl:ENSG00000180644
Fenofibrate Metabolite cas:49562-28-9
Fenofibrate Metabolite cas:49562-28-9

References

  1. Satterwhite T, Chua M-S, Hsieh S-C, Chang S, Scandling J, Salvatierra O, et al. Increased expression of cytotoxic effector molecules: different interpretations for steroid-based and steroid-free immunosuppression. Pediatr Transplant. 2003 Feb;7(1):53–8. PubMed Europe PMC Scholia
  2. Zarkhin V, Kambham N, Li L, Kwok S, Hsieh S-C, Salvatierra O, et al. Characterization of intra-graft B cells during renal allograft rejection. Kidney Int. 2008 Sep;74(5):664–73. PubMed Europe PMC Scholia
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  5. Sigdel TK, Li L, Tran TQ, Khatri P, Naesens M, Sansanwal P, et al. Non-HLA antibodies to immunogenic epitopes predict the evolution of chronic renal allograft injury. J Am Soc Nephrol. 2012 Apr;23(4):750–63. PubMed Europe PMC Scholia
  6. Heeger PS, Dinavahi R. Transplant immunology for non-immunologist. Mt Sinai J Med. 2012;79(3):376–87. PubMed Europe PMC Scholia
  7. Dragun D, Philippe A, Catar R. Role of non-HLA antibodies in organ transplantation. Curr Opin Organ Transplant. 2012 Aug;17(4):440–5. PubMed Europe PMC Scholia
  8. Stegall MD, Chedid MF, Cornell LD. The role of complement in antibody-mediated rejection in kidney transplantation. Nat Rev Nephrol. 2012 Nov;8(11):670–8. PubMed Europe PMC Scholia
  9. Roedder S, Kimura N, Okamura H, Hsieh S-C, 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;8(2):e56657. PubMed Europe PMC Scholia