First Aid, Chapter 1 Immune Mechanisms, Transplantation and Tumor Immunology

Question 1

What kind of rejection can ABO incompatibility cause in solid organ grafts? Why?

Answer 1

Hyperacute rejection.

• ABO blood group antigens are present on all tissues, including kidney and cardiac grafts.
• Preformed, naturally occurring antibodies to blood group substances are present in mismatched recipients.

Question 2

How are HLA antigens inherited?

Answer 2

In a Mendelian dominant manner.

Question 3

Why are HLA genes almost always inherited together? What is the fixed combination of genetic determinants called?

Answer 3

Because of the closeness of the different loci of the MHC and the resultant low cross-over frequency. The fixed combination is a haplotype.

Question 4

How many haplotypes does each individual receive? Why?

Answer 4

Since chromosome 6 is an autosome, all individuals have two expressed HLA haplotypes (maternal and paternal).

Question 5

How many possible haplotype combinations do offspring have of any two parents?

Answer 5

4

Question 6

What type of solid organic rejection can HLA mismatching cause? Why?

Answer 6

HLA antibodies—Individuals exposed to non-self-HLA antigens can develop anti-HLA antibodies. These antibodies, like ABO incompatibility, can cause hyperacute rejection of a solid organ expressing those HLA antigens.

Question 7

What methods are there to detect antibody mismatches between donor and recipient?

Answer 7

Serological cross matching and donor recipient matching via detecting HLA antigens either serologically or by DNA typing or measuring the response of immunocompetent cells from recipient to antigens present on donor cells

Question 8

What types of grafts is serologic cross-matching particularly important in? Why? What is screened for in serologic cross-matching? What type of transplant is positive serologic crossmatching an absolute contraindication for?

Answer 8

Important in kidney and heart because they are highly vascularized. Serum from the prospective recipient is tested against cells from the potential donor for presence of antibodies to RBC or HLA antigens. Positive serologic crossmatch is an absolute contraindication to renal transplantation.

Question 9

What type of graft rejection does antibodies to RBC and HLA cause?

Answer 9

Hyperacute graft rejection.

Question 10

How is donor-recipient matching done?

Answer 10

• Detect HLA antigens on donor and recipient leukocytes by either serologic or DNA typing.
• Measure response of immunocompetent cells from recipient to antigens present on donor cells (and vice versa for bone marrow transplantation).

Question 11

What types of transplants are not HLA matched and why?

Answer 11

Heart, lung, and liver transplants are often not HLA-matched (primarily due to time considerations).

Question 12

How are antigen mismatches detected in screening for organ transplant?

Answer 12

Antigen Mismatches = disparities that are serologically detected.

Question 13

How are allele mistmatches detected in screening for organ transplant?

Answer 13

Allele Mismatches = differences that can be identified only by DNA-based typing

Question 14

When does hyperacute rejection occur? What is the onset? What is the immune component that it is mediated by? What is the damage seen to the tissue?

Answer 14

-timing

Question 15

When does accelerated rejection occur? What is the onset? What is the immune component that it is mediated by? What is the damage seen to the tissue?

Answer 15

• Timing 3-5 days
• onset 1 day
• immune component: noncomplement fixing ab, NK cells, and monocytes
• vascular disruption and hemorrhage

Question 16

When does acute rejection occur? What is the onset? What is the immune component that it is mediated by? What is the damage seen to the tissue?

Answer 16

• timing 6-90 days
• onset days to weeks
• immune component: T lymphocytes (CD4+ and CD8+) and antibodies
• tubulitis, interstitial inflammation, parenchymal cell damage, and endovasculitis

Question 17

When does chronic rejection occur? What is the onset? What is the immune component that it is mediated by? What is the damage seen to the tissue?

Answer 17

• timing >60 days
• onset months to years
• Immune component Ab and inflammatory cytokines
• vascular onion skinning (fibrosis) on biopsy, along with delayed-type hypersensitivity (DTH) in vessel wall, intimal proliferation, and vessel occlusion.

Question 18

What post-op immunosuppression is used to reduce the risk of rejection?

Answer 18

Postoperative immunosuppression, using corticosteroids, antithymocyte globulin, tacrolimus, and cyclosporine is used to reduce the risk of rejection.

Question 19

Describe hyperacute rejection in histologic terms.

Answer 19

Hyperacute rejection in a transplanted kidney demonstrating acute tubular necrosis. All of the tubules are necrotic with sloughed pink epithelial cells and debris, with loss of nuclear detail.

Question 20

What is the chance of rejection of transplants in order from highest to lowest matching?

Answer 20

Mismatched
Matched unrelated
Matched 1st-degree relative
Syngeneic (identical twin)

Question 21

What are high-risk groups for hyperacute and accelerated rejection?

Answer 21

High-risk groups for hyperacute and accelerated rejection are multiparous women and multiple transfusion recipients.

Question 22

What types of transplant rejections does having preformed antibodies predict?

Answer 22

Hyperacute and accelerated rejection.

Question 23

How is screening for preformed antibodies done?

Answer 23

• Pretransplant screen for presence of antidonor HLA antibodies to panel of potential donors
• Expressed as percentage of reactive antibodies (PRA)

Question 24

How do antibodies cause graft rejection? What type of rejection is it involved it

Answer 24

• Antibodies combine with HLA antigens on endothelial cells with subsequent complement fixation and accumulation of polymorphonuclear cells.
• Endothelial damage then occurs secondary to enzymes released form polymorphonuclear (PMN) leukocytes.
• Platelets later accumulate, thrombi develop, and the result is renal cortical necrosis or myocardial infarction.
• hyperacute rejection, particularly of highly vascularized organs such as kidney and heart.

Question 25

How is innate immunity involved in graft rejection? What cells are involved? What type of rejection?

Answer 25

Innate Immunity—Natural killer cells and monocytes are effector cells of accelerated rejection via antigen-dependent cell-mediated cytotoxicity (ADCC).

Question 26

How do leukocytes and cytokines impact allograft rejection?

Answer 26

• Allograft rejection results from coordinated activation of alloreactive T lymphocytes and APCs.
• Primed helper T lymphocytes release multiple cytokines: IL-2, IL-4, IL-5, IL7, IL-10, IL-15, TNFα, and IFNγ.
• Cause recruitment of primarily immunocompetent donor-specific CD4+ T lymphocytes; also CD8+ cytotoxic T lymphocytes, antibody-forming B lymphocytes, and nonspecific inflammatory cells.

Question 27

Stimulation of CD4+ T lymphocytes through antigen receptor is not sufficient to initiate T-lymphocyte activation. What else is needed?

Answer 27

Activation of CD4+ T lymphocytes needs costimulation.

-Signaling must occur through one of the costimulators:
o Receptor: Ligand interactions (Table 1-30)
o IL-1 and IL-6 on APCs

Question 28

How does tolerance of grafts occur via T cells?

Answer 28

Tolerance induction occurs when T-cell receptor interacts with APCs. As a result, T–lymphocyte-accessory proteins and ligands on APCs are target molecules for antirejection therapy.

Question 29

What are the ligands on APCs for the following receptors on T lymphocytes? 
CD2
CD11a/CD18
CD5
CD40L
CD28

Answer 29

CD2: CD58 
CD11a/CD18: CD54 
CD5: CD72 
CD40L: CD40 
CD28: CD80 or CD86

Question 30

How are CD8+ T lymphocytes activated in graft rejection? What role do CD8+ T lymphocytes play in graft rejection?

Answer 30

CD8+ T lymphocytes recognize antigenic peptides on MHC class I molecules and represent a major cytotoxic effector lymphocyte population in graft rejection.

• CD8+ activation requires second signal + IL-2.
• CD8+ activation signaling occurs through γ chain of multiple cytokine receptors.
• Activated CD8 cells proliferate and mature into specific alloreactive clones capable of releasing granzymes, perforin, and toxic cytokines such as TNFα.

Question 31

Describe the steps that lead to graft rejection after T lymphocyte activation occurs?

Answer 31

• Autocrine T-lymphocyte proliferation continues secondary to expression of IL-2R. The IL-2 or IL-2R interactions trigger kinases, leading to Raf-1 activation and expression of DNA binding proteins, Jun, c-Fos, and c-Myc. This results in graft-specific T lymphocytes.
• T-lymphocyte cytokines also activate macrophages, leukocytes, and upregulate HLA on graft cells.
• Activated T lymphocytes stimulate B lymphocytes to make autograft antibody.
• Ultimately, all cellular and humoral factors destroy graft.

Question 32

How do cyclosporine and tacrolimus interfere with graft rejection?

Answer 32

Cyclosporine and tacrolimus interfere with activating process involving T-cell receptors and costimulatory molecule CD28:CD80 or CD86.

Question 33

Describe the mechanism of Cyclosporin and tacrolimus in management of graft rejection?

Answer 33

Cyclosporin binds to cyclophilin → inhibition of calcineurin → blockade of NFAT activation → inhibition of transcription of IL-2 → inhibition of T-cell differentiation

Question 34

What is the mechanism of rapamycin in management of graft rejection?

Answer 34

Rapamycin binds to FKBP → binds to mTOR → inhibition of mTOR → blockade of T-cell proliferation

Question 35

How does mycophenolate mofetil (MMF) inhibit graft rejection?

Answer 35

Inhibition of guanine nucleotide synthesis → T-cell proliferation halted

Question 36

How does azathioprine inhibit graft rejection?

Answer 36

Blockade of lymphocyte precursors (less-specific than MMF → higher toxicity)

Question 37

What are drugs in the category of metabolic toxins that inhibit proliferating T cells?

Answer 37

Mycophenolate mofetil (MMF) and azathioprine

Question 38

What are drugs that are inhibitors of T lymphocytes and their activation?

Answer 38

Cyclosporin (CsA), FK 506 (tacrolimus), and rapamycin

Question 39

What are drugs that are antibodies to T cell antigens?

Answer 39

Anti-CD3 and Anti-CD25 (a subunit of IL2R)

Question 40

What is the mechanism of action of anti-CD3 in management of graft rejection?

Answer 40

Monoclonal Ab binding to CD3 → promote phagocytosis or complement-mediated lysis of T cells

Question 41

What is the mechanism of action of Anti-CD25 (a subunit of IL2R) in management of graft rejection?

Answer 41

Blockade of IL-2 binding to activated T cells that express CD25 → prevention of T-cell activation

Question 42

What is the mechanism of corticosteroids in management of graft rejection?

Answer 42

Block synthesis and secretion of cytokines from macrophages

Question 43

What cells are early tumor lesions infiltrated with?

Answer 43

Early lesions are infiltrated with hematopoietic cells, including lymphocytes, macrophages, and occasionally granulocytes.

Question 44

What cells are in tumor lesions in late stages of tumor development in colon, breast, and oral carncinomas? Describe the cells and the markers on the cells.

Answer 44

An abundance of tumor infiltrating lymphocytes (TILs).

o TILs: Small-to-large lymphocytes that are mostly CD3+ CD95+ TCR-α/β + T lymphocytes.

Question 45

The presence of what chain in tumor infiltrating lymphocytes is associated with improved patient survival? Why? What marker is present on these cells?

Answer 45

The presence of the TILs with a normal ζ chain is associated with improved patient survival. This results in normal signaling through the TCR. These cells are typically CD95+ (Fas).

Question 46

Cyclosporin inhibits calcineurin and blocks NFAT activation by binding to which molecule?

Answer 46

Cyclophilin

Question 47

What does TNF induce apoptosis through?

Answer 47

TNF family receptors. Include FasL, TRAIL, and TNF.

Question 48

What immunoinhibitory cytokines do tumors produce?

Answer 48

TGFβ, IL-10, GM-CSF, and ζ-inhibiting protein (ZIP).

Question 49

What immunoinhibitory small molecules do human tumors produce? How do they inhibit leukocytes?

Answer 49

Prostaglandin E2, epinephrine, and reactive oxygen metabolites (ROMs). Inhibit leukocyte functions via increased cyclic adenosine monophosphate (cAMP) or superoxide generation.

Question 50

What virally related immunohibitory products do human tumors produce?

Answer 50

p15E and EBI-3

Question 51

What do tumor-associated gangliosides do?

Answer 51

Inhibit IL-2-dependent lymphocyte proliferation, induce apoptotic signals, suppress NFkB activation, and interfere with dendritic cell generation.

Question 52

Are tumors ignored by the immune system? In what ways?

Answer 52

No.

• Cancer patients have a higher amount of tumor-specific T lymphocytes in circulation that recognize class I or class II MHC-restricted tumor epitopes.
• Tumor-specific T lymphocytes, in the presence of cytokines, can increase and target tumor cells for destruction.
• Tumor-specific T lymphocyte can be used to recognize T–lymphocyte-defined tumor epitopes.
• Antitumor antibodies in patients allow for identification of serologically defined tumor antigens.

Question 53

How do NK cells prevent metastases?

Answer 53

NK cells are important in preventing metastasis of tumors by eliminating tumor cells in the circulation through perforin-mediated lysis and apoptosis of tumor cell targets.

Question 54

What are killer cell immunoglobulin-like receptors (KIR)?

Answer 54

Inhibitor receptors on NK cells known as killer cell immunoglobulin-like receptors (KIR) recognize MHC class I and assist NK cells in sampling healthy cells to look for abnormal cells that have lost the self-determinants on their surface.