Flashcards in T Cell Mediated Transplant Rejection Deck (25):
Define allogeneic, Syngeneic, Xenogeneic, Autologous
Allogenic: Same species, different alleles
Syngeneic: Same species, Same alleles
Xenogeneic: Different species, different alleles
Autologous: Same individual
Describe MHC class 1
Made of two polypeptide chains;
1. Alpha chain (Polymorphic): Binds antigen. Encoded by HLA genes
2. Beta 2 microglobulin chain (Non-polymorphic): Provides support to alpha chain.
Describe MHC class 2
Made of two polypeptide chains:
1. Alpha chain (polymorphic): Encoded by HLA-DPA, DQA and DRA
2. Beta chain (polymorphic): Encoded by HLA-DPB, DQB, and DRB
What are the rules of pairing MHC class 2 polypeptide chains?
1. Alpha chains only pair with beta chains.
2. Alpha chains made by HLA-DPA only pair with beta chains made by HLA-DPB to make HLA-DP; same goes for HLA-DR and DQ.
Discuss allorecognition of MHC
MHC self peptide is recognized by TCR as foriegn and produces an immune response.
What are some important features of MHC?
1. Co-dominant expression; Both parents are expressed equally.
2. Polymorphic genes
3. MHC expressing cell types (class 1 and 2)
Describe the variability of MHC on the molecular level?
6 different MHC class 1 alleles can be expressed on a cell. 6-8 different MHC class 2 alleles can be expressed on a cell.
Discuss direct allorecognition
The recipient's alloreactive T cells are activated by donor APC's.
1. After transplantation, donor DCs go to lymph node and present donor peptide to TCRs on naive mature T cells; Causes cross reactivity
Discuss the two options in indirect allorecognition.
Option 1: Donor cells circulate through lymph to draining lymph node and are phagocytosed by DCs
Option 2: Recipient DCs migrate into donor organs, phagocytose donor cells and then migrate back to lymph node.
What causes most graft rejections?
Recipient TCRs recognizing processed donor MHC proteins (polymorphic) as foreign.
How are the 3 types of rejections categorized?
1. How long it took to reject the tissue.
2. Pathology of rejected tissue
3. Leukocytes/proteins that mediate the rejection.
Discuss Hyperacute rejection
1. Occurs within minutes to hours following transplantation.
2. Characterized by thrombus formation in graft vasculature
3. Mediated by preexisting alloreactive antibodies in recipient circulation.
How does Hyperacute rejection happen?
Recipient's circulating alloreactive IgM or IgG binds to antigens on donor's endothelial cells; Activates platelets and causes thrombus formation.
What are the characteristics of and acute rejection?
1. Occurs within days to weeks following transplantation.
2. Thrombus formation in graft vasculature
3. Mediated by recipient's alloreactive T cells.
How does Acute rejection happen.
Alloreactive T cells are activated by direct or indirect allorecognition. Recipient's alloreactive CD8s destroy graft and graft parenchyma, Th1s are also activated and then activate B cells to make alloreactive antibodies; Thrombus formation.
What are the characteristics of Chronic rejection? (most common)
1. Within months or years following transplantation.
2. Characterized by fibrosis in graft, Occlusion of vasculature (kidney/heart), Thickened airways (lung) and non-functional ducts (liver)
3. Mediated by alloreactive T cells and alternatively activated macrophages.
How does chronic rejection happen?
Alloreactive CD4s secrete cytokines that stimulate proliferation of endothelial cells leading to graft arteriosclerosis. Chronic activation of alternatively activated macrophages promote wound healing and lead to fibrous tissue.
Discuss Graft vs Host Disease
Occurs in tissues containing large numbers of leukocytes (eg bone marrow). Graft immune cells attack recipient.
Acute: epithelial cell death in skin, liver, and GI tract
Chronic: Fibrosis and atrophy of organs.
How do you prevent hyperacute rejection?
Matching blood types
How do you prevent acute and chronic rejection?
Mixed lymphocyte reaction; Mix lymphocytes from donor and recipient. If donor lymphocytes proliferate and secrete cytokines then don't transplant. OR match MHC alleles.
Whats the mechanism of action for cyclosporine/tacrolimus?
Blocks T cell cytokine production by inhibiting NFAT transcription factor.
Whats the MOA for Rapamycin?
Block lymphocyte proliferation by inhibiting mToR and IL-2 signaling.
Whats the MOA for corticosteroids?
Reduces inflammation by effects on multiple cell types.
What is the MOA for Anti-IL2 receptor antibody?
Inhibits T cell proliferation by blocking IL-2 binding.