FMS Week 10: Transplantation Flashcards
1
Q
Transplantation Definition
A
Transplantation is the process of taking cells, tissues, or organs, called a graft, from one individual (donor) and placing them into an individual (Recipient)
2
Q
Autograft Definition
A
from one part of the body to another e.g. trunk to arm
3
Q
Isograft Definition
A
between genetically identical individuals (e.g. monozygotic twins, or within an inbred strain)
4
Q
Allograft Definition
A
between different members of the same species (e.g. Mr. Smith to Mr. Jones)
5
Q
Xenograft Definition
A
between members of different species (e.g. monkey to man)
6
Q
HLA Mismatches AKA
A
Alloantigens
7
Q
HLA Mismatches can lead to …
A
Transplant Rejection
8
Q
Types of transplant rejection
2 listed
A
- Transplant Rejection
- Host-versus-Graft Disease
9
Q
HLA Class I is expressed on what cells
A
HLA Class I is expressed on all nucleated cells
10
Q
HLA Class II is expressed on which cells?
A
HLA Class II is expressed on Professional Antigen Presenting Cells (APCs) such as
- Dendritic Cells (DCs)
- Macrophages (Monocytes)
11
Q
HLA Class II is upregulated on?
A
Endothelial cells
12
Q
Type of HLA expression
A
Co-dominant expression
13
Q
Co-dominant expression definition
A
Maternal and Paternal alleles are fully expressed
14
Q
MHC alleles are on which chromosome?
A
Chromosome 6
15
Q
MHC Class II Haplotypes
3 listed
A
- HLA-DP
- HLA-DQ
- HLA-DRB1
16
Q
MHC Class I Haplotypes
3 Listed
A
- HLA-B
- HLA-C
- HLA-A
17
Q
Main ways to be exposed to HLA proteins
3 listed
A
- Transfusion
- Pregnancy
- Transplant
18
Q
3 Pathways of allorecognition
A
- Direct
- Semi-Direct
- Indirect
19
Q
Direct Allorecognition Mechanism
A
Recipient T cell recognizes self or non-self peptide represented on non-self MHC from a donor APC
20
Q
Semidirect Allorecognition Mechanism
2 listed
A
- Recipient T cell recognizes non-self peptides on self MHC on Recipient APC
- Recipient T Cell Recognizes self peptide on non-self MHC on Recipient APC
21
Q
Indirect Allorecognition Mechanism
A
Recipient T cell recognizes non-self peptide on self MHC on recipient APC
22
Q
Direct Allorecognition accounts for what % of Allorecognition?
A
1-10%
23
Q
Indirect Allorecognition accounts for what % of Allorecognition?
A
< 0.1 %
24
Q
Semidirect Allorecognition accounts for what % of Allorecognition?
A
~90%
25
Direct Allorecognition Donor or Recipient APC?
Donor APC
26
Semidirect Allorecognition Donor or Recipient APC?
Recipient APC
27
Indirect Allorecognition Donor or Recipient APC?
Recipient APC
28
Mixed Lymphocyte Reaction Steps
4 listed
* Mix blood mononuclear cells from two donors in tissue culture
* Responder T cell recognition of allogeneic MHC Class I & II molecules
* Clonal expansion and functional differentiation of responder T cells
* Effector functions of both CD8 and CD4 T cells
29
Mixed Lymphocyte Reaction: MHC Class I Interactions and Result
4 Listed
* Recipient CD8 T Lymphocyte (Responder cell) recognizes MHC Class I presented on allogeneic Donor APC
* Recipient allogeneic CD8 CTLs are activated
* Allogeneic CTLs kill and lyse target cell expressing allogeneic MHC
30
Mixed Lymphocyte Reaction: MHC Class II Interactions and Result
4 Listed
* Recipient CD4 T Lymphocyte (Responder cell) recognizes MHC Class II presented on allogeneic Donor APC
* Recipient allogeneic CD4 Helper T cells are activated
* Allogeneic Helper T Cells secrete cytokines when contacting Allogeneic Donor MHC Class II
31
Immunological Components of Rejection
SEE LATER
32
Types of Rejection Reactions of Solid Organ Transplants
4 Listed
* Hyperacute
* Accelerated
* Acute
* Chronic
33
Hyperacute rejection timeline
minutes-hours
34
Hyperacute Rejection Cause
Preexisting anti-donor antibodies in the recipient and complement
35
Accelerated Rejection Timeline
Days
36
Accelerated Rejection Cause
Reactivation of sensitized lymphocytes against donor antigens (memory response)
37
Acute Rejection Timeline
Days-weeks/months
38
Acute Rejection Cause
Primary activation of lymphocytes against donor antigens (de novo)
39
Chronic Rejection Timeline
months-years
40
Chronic Rejection Causes
5 listed
* HMI
* CMI
* Cytokines
* Immune Complexes
* Fibrosis
41
HMI AKA
Humoral Immunity
42
CMI AKA
Cell-Mediated Immunity
43
Hyperacute Graft Rejection
4 Steps
44
Acute Cell-mediated Rejection Allorecognition Type
Direct Recognition
45
How are organ's dendritic cells activated in Acute Rejection?
The inflamed state of the organ activates the donor dendritic cells
46
Acute Cell-mediated Rejection
4 Steps
47
Acute Cell-mediated Rejection can result in?
3 Listed
* Parenchymal cell damage
* interstitial inflammation
* Endotheliatitis
48
Acute Cell-mediated Graft Rejection: Tubulointerstitial Pattern Description
Inflammatory cells in the interstitium and between epithelial cells of the tubules (tubulitis)
49
Acute Cell-mediated Graft Rejection: Vascular Pattern Description
Rejection vasculitis, with inflammatory cells attacking and undermining the endothelium (endotheliitis)
50
Most Common pattern of Cell-mediated Acute Rejection
Tubulointersitial Pattern
51
Acute Rejection is __________ Mediated.
Antibody &/or T Cell
52
Acute Rejection can involve?
Antibodies and T cells
53
Acute Humoral Rejection of kidney graft can result in?
3 listed
* Rapid decline in urine output,
* Rise in serum Creatinine,
* Tenderness and edema of graft
54
Acute Humoral Rejection associated pathologies
2 listed
* Inflammation in peritubular capillaries (capillaritis)
* Immunoperoxidase stain - C4d deposition in peritubular capillaries and a glomerulus
55
Chronic Rejection Allorecognition Type
Indirect Allorecognition
56
Chronic Rejection occurs after how much time post-transplant?
Months or years
57
Chronic Rejection Vascular Effects
3 listed
* Proliferative inflammatory lesions of the small arteries, thickening of the glomerular basement, and interstitial fibrosis lead to vasculature changes and loss of function
* Vascular changes often due to T cell-mediated damage and antibody against HLA alloantigen(s)
* Vascular occlusion & Interstitial fibrosis
58
Chronic Rejection histopathologic effects
4 listed
59
Immunosuppressive Drugs Basic Categories
3 Listed
* Anti-inflammatory
* Inhibition of signaling pathways of T cell activation
* Cytotoxic; interfere with DNA replication
60
61
solid organ transplant
62
Cyclosporine and Tacrolimus Mechanism of Action
Blocks T cell cytokine production by inhibiting the phosphatase calcineurin and thus blocking activation of the NFAT transcription factor
63
Mycophenolate Mofetil Mechanism of Action
Blocks lymphocyte proliferation by inhibiting guanine nucleotide synthesis in lymphocytes
64
Rapamycin (Sirolimus) Mechanism of Action
Blocks lymphocyte proliferation by inhibiting mTOR and IL-2 signaling
65
Corticosteroids Mechanism of Action
Reduce inflammation by effects on multiple cell types
66
Antithymocyte Globulin Mechanism of Action
Binds to and depletes T cells by promoting phagocytosis or complement-mediated lysis (used to treat acute rejection)
67
Anti-IL-2 Receptor (CD25) Antibody Mechanism of Action
2 listed
* Inhibits T cell proliferation by blocking IL-2 binding
* may also opsonize and help eliminate activated IL-2R-expressing T cells
68
CTLA4-Ig Mechanism of Action
Inhibits T cell activation by blocking B7 costimulator binding to T cell CD28
69
Anti-CD52 (alemtuzumab) Mechanism of Action
Depletes lymphocytes by complement-mediated lysis
70
HLA Testing for Solid Organ Transplant
5 listed
1. Tissue Typing - Recipient
2. HLA Antibody Testing - Recipient
3. Tissue Typing Donor
4. Flow-Based Crossmatch
5. Post-Transplant Monitoring
71
Tissue Typing - Recipient Purpose
Determine HLA molecules the recipient expresses
72
HLA Antibody Testing - Recipient Purpose
2 Listed
* Does the recipient have HLA antibody (Screen)
* What is the specificity of each HLA antibody? (Identification)
73
Tissue Typing - Donor Purpose
3 Listed
* Determine HLA molecules the donor expresses
* Determine HLA mismatch antigens with recipient
* Does the recipient have donor-specific antibody (DSA)?
74
Flow-Based Crossmatch Purpose
2 Listed
* Donor cells + recipient serum
* Does DSA cause reactivity?
75
DSA AKA
Donor-specific Antibody
76
Post-Transplant Monitoring Purpose
Does the recipient have DSA?
77
Hematopoietic Stem Cell Transplantation are performed on who?
transplants are performed to treat patients with life-threatening malignant and non-malignant disease
78
Hematopoietic Stem Cell Transplantation Treatment Reasons
5 listed
* Rescue of marrow after irradiation/chemotherapy
* Immunotherapy against a neoplasm
* Treating a bone marrow failure
* Treating an immune system disorder
* Treating an inherited metabolic disorder
79
Goals of Hematopoietic Stem Cell Transplantation
2 listed
1. Rid recipient of disease
2. reconstitute immune response
80
Hematopoietic Stem Cell Transplantation Process 3 steps
81
Hematopoietic Stem Cell Transplantation: Relative time of recovery for Neutrophils, macrophages, eosinophils, and basophils?
1-2 months
82
Hematopoietic Stem Cell Transplantation: Relative time of recovery fro Natural Killer Cells
3-4 Months
83
Hematopoietic Stem Cell Transplantation: Relative time to recovery T cells
6-12 months
84
Hematopoietic Stem Cell Transplantation: Relative time to recovery B cells
12-24 months
85
Clinical Outcomes of Bone Marrow Transplant Correlates with?
86
MiHA
Minor Histocompatibility Antigens
87
Patients recieving HLA identical Bone Marrow can still get?
GVHD
88
Minor Histocompatibility Antigens role in GVHD
* Polymorphic self-proteins (non-HLA) that differ in amino acid sequence between individuals can lead to GVHD
* Processed and presented by APC and recognized by T cells as non-self since T cells were never selected to be tolerant for them
89
GVHD Steps
3 Listed
90
Pathophysiology of GVHD
3 listed
91
Acute GVHD after HSCT
92
Chronic GVHD after HSCT
93
HSCT AKA
Hematopoietic Stem Cell Transplantation
94
GVHD
95
HSC grafts depleted of T cells reduce?
But
May also compromise what?
2 listed
96
NK cells AKA
Natural Killer Cells
97
How do NK cells contribute to GVL effects?
3 things listed
98
Alloreactive NK cells can reduce the incidence of?
Leukemic Relapse
99
HLA Testing for solid organ transplant example
100
Direct Allorecognition summary
is unique to transplantation and refers to the recognition by recipient T cells of intact donor HLA/peptide complexes expressed on the surface of graft-derived antigen presenting cells (APC)
101
Indirect Allorecognition summary
refers to the recognition by recipient T cells of processed donor HLA molecule presented by recipient HLA molecules
102
Semi-direct Allorecognition summary
Involves the acquisition by recipient APCs of donor exosomes (and likely other extracellular vesicles) released by passenger leukocytes or the graft
103
During the development of aGVHD
activation of various immune cells, especially donor T cells, leads to damage of target organs including skin, liver, lungs and gut
104
aGVHD AKA
Acute Graft Versus Host Disease
105
cGVHD AKA
Chronic Graft Versus Host Disease
106
cGVHD Pathology
2 listed
* Thymic destruction, wither from pretransplant conditioning or aGVHD, and chronic stimulation of donor T cells contribute to cGVHD
* widespread tissue fibrosis
107
GVL effect
when alloreactive T/NK cells in the graft help to rid the patient of residual leukemia cells
