T Cell Mediated Transplant Rejection

Question 1

Define allogeneic, Syngeneic, Xenogeneic, Autologous

Answer 1

Allogenic: Same species, different alleles
Syngeneic: Same species, Same alleles
Xenogeneic: Different species, different alleles
Autologous: Same individual

Question 2

Describe MHC class 1

Answer 2

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.

Question 3

Describe MHC class 2

Answer 3

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

Question 4

What are the rules of pairing MHC class 2 polypeptide chains?

Answer 4

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.

Question 5

Discuss allorecognition of MHC

Answer 5

MHC self peptide is recognized by TCR as foriegn and produces an immune response.

Question 6

What are some important features of MHC?

Answer 6

1. Co-dominant expression; Both parents are expressed equally.
2. Polymorphic genes
3. MHC expressing cell types (class 1 and 2)

Question 7

Describe the variability of MHC on the molecular level?

Answer 7

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.

Question 8

Discuss direct allorecognition

Answer 8

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

Question 9

Discuss the two options in indirect allorecognition.

Answer 9

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.

Question 10

What causes most graft rejections?

Answer 10

Recipient TCRs recognizing processed donor MHC proteins (polymorphic) as foreign.

Question 11

How are the 3 types of rejections categorized?

Answer 11

1. How long it took to reject the tissue.
2. Pathology of rejected tissue
3. Leukocytes/proteins that mediate the rejection.

Question 12

Discuss Hyperacute rejection

Answer 12

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.

Question 13

How does Hyperacute rejection happen?

Answer 13

Recipient’s circulating alloreactive IgM or IgG binds to antigens on donor’s endothelial cells; Activates platelets and causes thrombus formation.

Question 14

What are the characteristics of and acute rejection?

Answer 14

1. Occurs within days to weeks following transplantation.
2. Thrombus formation in graft vasculature
3. Mediated by recipient’s alloreactive T cells.

Question 15

How does Acute rejection happen.

Answer 15

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.

Question 16

What are the characteristics of Chronic rejection? (most common)

Answer 16

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.

Question 17

How does chronic rejection happen?

Answer 17

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.

Question 18

Discuss Graft vs Host Disease

Answer 18

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.

Question 19

How do you prevent hyperacute rejection?

Answer 19

Matching blood types

Question 20

How do you prevent acute and chronic rejection?

Answer 20

Mixed lymphocyte reaction; Mix lymphocytes from donor and recipient. If donor lymphocytes proliferate and secrete cytokines then don’t transplant. OR match MHC alleles.

Question 21

Whats the mechanism of action for cyclosporine/tacrolimus?

Answer 21

Blocks T cell cytokine production by inhibiting NFAT transcription factor.

Question 22

Whats the MOA for Rapamycin?

Answer 22

Block lymphocyte proliferation by inhibiting mToR and IL-2 signaling.

Question 23

Whats the MOA for corticosteroids?

Answer 23

Reduces inflammation by effects on multiple cell types.

Question 24

What is the MOA for Anti-IL2 receptor antibody?

Answer 24

Inhibits T cell proliferation by blocking IL-2 binding.

Question 25

Whats the MOA for CTLA4-Ig?

Answer 25

Inhibits T cell activation by blocking B7 costimulator binding to CD28