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Immunology Exam 3 > Lecture 20: Transplantation Immunology > Flashcards

Lecture 20: Transplantation Immunology Flashcards

1
Q

Differentiate b/w autograft, isografts, allografts, xenografts.

Which one is most susceptible to rapid attack by naturally occuring Abs and complement?

A

Autograft - from one part to anothe rpart of same individual

Isograft - b/w diff individuals of ID genetic makeup –> ID twins

Allografts - b/w nonidentical members of same species

Xenografs - b/w members of different species

  • this type is most susceptible to rapid attack by naturally occuring Abs and complement
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2
Q

What are 3 major conclusions recognizing graft rejection is an immune reaction?

A
  1. Graft rejection shows MEMORY and SPECIFICITY = 2 key key features of adaptive immunity
  2. Mediated by lymphocytes
  3. Can be mediated by T lymphocytes
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3
Q
  1. How are HLA Ag expressed?
  2. Which class are particularly strong barriers to transplantation?
  3. What are the 3 most important paris of Class II HLA?
A
  1. Co-dominantly
  2. Class I (HLA-A and HLA-B) bc every cell in body expresses Class I
  3. HLA-DR, HLA-DP and HLA-DQ
    * Class II HLA are only on professional APCs
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4
Q

Direct vs Indirect Allorecognition

  1. Which pathway is: donor APC –> Recipient T cell?
  2. Which is recipient APC –> Recipient T cell?
  3. Which pathway is more important for chronic rejection?
A
  1. Direct
    * TCR on recipient T cells directly recog. the donor MHC mlcls
  2. Indirect
  • recipient T cells recognize donor MHC mlcls that were processed by recipient APCs
  • donor MHC mlcls are present as peptides in context of recipient Class I and II MHC
  1. Indirect
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5
Q

What are the 4 variables/key concepts that determine transplant outcome?

A
  1. Condition of the allograft
  2. Donor-host antigenic disparity (want low as possible)
  3. Strength of host anti-donor response
  4. Immunosuppressive regimen
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6
Q

Condition of the Allograft:

  1. What is cold ischemia time?
  2. When transplanted, the damaged graft tissues release what? This release results in tissue damage.
  3. Clotting cascade generates what? These then activate which 2 cell types? What is the clinical result of this response?
  4. Kinin cascade produces what? What are the 3 key clinical responses to this mlcl?
  5. If these early pro-inflammatory responses go uncontrolled what results?
A
  1. Time that the organ is w/o blood and is kept cold, from the time the organ was initially removed from donor to time its transplanted into recipient
    * more time –> more ischemia reperfusion damage
  2. mediators
  3. Fibrinopepties –> activates mast cells and endothelial cells
    * inc. local vascular permeability and neutrophil/MΦ
  4. Bradykinin
    * vasodilation, sm. m contraction, inc. vascular permeability
  5. allograft rejection
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7
Q

During Donor-recipient workup, what is first established?

A

ABO blood group compatibility

  • ABO = barrier to transplantation of solid organ
  • Abs to A and B are in ppl w/o these Ags on their RBCs
  • ABO matichg is not important for:
    • corneal or heart valve transplations
    • bone and tendon grafts
  • Blood group Ags also expressed on renal and endothelium
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8
Q

For each RBC type, Group A, B, AB, and O, what is their corresponding Ag and Ab?

A

Group A RBC:

  • Ag A
  • Anti-B abs

Group B RBC:

  • Ag B
  • Anti-A abs

Group AB RBC:

  • Ag A/B
  • no abs

Group O RBC:

  • no Ag
  • Anti-A/B abs
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9
Q

ABO Compatibility

Patient with A group:

Patient with B group:

Patient w/ AB group:

Patient w/ O group:

A

A group:

  • compatible plasma: A, AB
  • compatible washed RBCs: A and O

B group:

  • compatible plasma: B and AB
  • compatible washed RBCs: B and O

AB group:

  • compatible plasma: AB
  • compatible washed RBCs: O, A, B, AB

O group:

  • compatible plasma: O, A, B, AB
  • compatible washed RBCs: O
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10
Q

During donor recipient workup what is used to identify HLAs?

What is a successful transplantaion dependent on?

A

Tissue Typing

MHC Ags

  • this is required due to extreme polymorphorism of HLA (human leukocyte Ag complex)
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11
Q
  1. What serology test identifies matching of Class I MHC/HLA b/w donor and recipient?
  2. What is the mechanism behind this (think big picture)?
  3. What are the primary sources for the lymphocytes?
A
  1. Microcytotoxicity
  2. Complement-dependent serology
  • antisera contain Ab’s to HLA Ags
  • Abs bind to HLA Ag creating Ag-Ab complex
    • activating CLASSICAL complement pathway resulting in lymphocyte lysing
  • Lysing is detected by staining the cells
  1. Spleen and LN
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12
Q

Microcytotoxicity Test main 3 steps are (ie what is added during each step)?

How do you determine if the pt and donor are matches?

A
  • Step 1 = Add Abs
  • Step 2 = Add complement
    • complement forms pores in cells via MAC
  • Step 3 = Add dye
    • dye can’t go in unless the MAC has created holes/pores

HLA is ID if both cells show dye accumulation

if dye is only present in donor –> no match–> HLA Ag non-ID

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13
Q
  1. What is needed to prevent hyperactive Ab-dependent rejection of graft?
  2. What is this testing for?
  3. What would the test used to carry this out?
A
  1. Cross-matching
  2. Used to test recipient serum for PREFORMED Abs against donor’s HLAs
    * pre-existing Abs due to prev. exposure of pathogen
  3. Microcytotoxicity (modified) test
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14
Q

During microcytotoxicity test for preformed Abs, what result would indicate the donor can be used safely without causing a hyperactive rejection?

A

If there are no Abs in recipient, the donor cells are are not stained (aka there is no damage to the cell) and they are a good match.

Steps for this test:

  • start with donor cells
  • add recipient serum
    • recipient abs in serum bind to donor cell
  • add complement
  • add dye
  • IF dye accumulates in cell –> preformed Abs are present and would result in hyperactive rejection
  • IF no dye in donor cell –> no preformed Abs are present and the potential donor is ID
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15
Q
  1. Mixed lymphocyte reaction is used in what kind of HLA typing?
  2. Is this a one or two way rxn?
  3. Lymphocytes from the donor are called what? What do these serve as?
  4. Lymphocytes from the recipient are called what?
  5. What is measured by incorporation of tritated thymidine?
A
  1. Class II
  2. Two way rxn
  3. Stimulator cells; serve as APC of Class II MCH Ags
    * these are initially irradiated to stop their proliferation
  4. Responder cells
    * these will be activated by MISMATCHED class II MHC –> then proliferate
  5. Prolieration (ie response)
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16
Q

During MLR what indicates the donor and recipient Class II MHC Ags are the same?

A

No proliferation will occur –> radioactivity is NOT incorporated in DNA cells

Not a match –> radioactivity incorporated in DNA quantifying cell prolieferation

17
Q
  1. What is the difference b/w Host vs. Graft (HVG) dz and Graft vs Host (GVH) dz?
  2. What are the 3 types of HVG dz?
  3. What is the most important thing to remember when trying to determine type of rejection?
A
  1. HVG = recipient cell attacks donor (ie the transplant)

GVH = donor T cells in graft proliferate and attack recipients tissue

  1. hyperacute, acute, and chronic
  2. Timeframe of onset of sx
18
Q

Hyperacute HVG rejection ouccurs _______.

  1. What is the mechanism?
  2. What complement system is activated?
A

Immediatedly (ie upon operation –> thrombosis and occulusion of graft vessels)

1. Preformed Abs directed against donor tissue, caused by:

  • ABO incompatibility (primary)
  • recipient is sensitized to donor MHC by previous transplants, mutliple transfusions, or pregnancy
  1. CP –> Abs bind edothelial cells activating CP –> lead to death of endothelium

(**pre-existing Abs bind endothelial cells lining blood w/in min to hours*)

19
Q

Acute HVG rejection occurs in ____ to ____.

  1. What is the mechanism?
  2. Is this direct or indirect allogenic presentation?
A

Days - weeks

  1. T cell mediated IR against foreign MHC
  • following transplantation donor DCs migrate to LN draining the organ and stim. 1° recipient response
  • both CD4+ and CD8+ T cells can cause graft rejection
  • inflammation and leukocyte infiltration of graft vessels occurs
  1. Direct allogenic presentaiton

most common type

20
Q

Chronic HVG rejection occurs in ____ to ____.

  1. What is the mechanism?
  2. Is this direct or indirect allogenic presentation?
  3. Chronic rejection does not respond to?
A

Months - years

  1. T cell mediated process
    * causes intimal thickening, fibrosis, and occlusion of graft vessels –> ischemia of organ
  2. Indirect presentation (DC of recipient take tissue debris from donor tisse to the LN and activate receipient T cells)
  • Abs can also be involved –> deposition of complement in graft tissues
  • non-immunologic factors:
    • ischemia-reperfusion damage
    • recccurance of dz that fuased failure of own kidney
    • nephrotoxic drugs

3. Immunosuppressive therapy

21
Q
  1. Why is the IR against a graft much more vigorous and strang than seen against a pathogen?
  2. What type of interaction b/w TCR and MHC mlcls allows for answer to q1?
A
  1. Higher frequency of T cells recognizing the graft as foreign
    * 1:100 - 1:1000 T cells response to allogenic APCs (specific against particular HLA
  2. Low affinity interactions –> which are compensated for by mutiple interactions providing an avidity advantage

Immune memory of previous encounters w/ donor Ags is also impt

22
Q

HVG:

  1. What are non-immune injuries to the graft called and what do these allow?
  2. What effector cell type provides humoral rejection? via which cytokines?
  3. What effector cell type provides the cellular rejection? via which cytokines?
  4. Which of these is MOST IMPT for ACUTE and CHRONIC T cell mediated responses?
A
  1. Danger signals –> activate endothelial cells and T cells enter the allograft
  2. Th2 –> IL-4, IL-5 and IL-10
  3. Th1 –> IL-2 and IFN-γ
  4. Th1
23
Q
  1. With what kind of transplants does GVH dz often occur in?
  2. What causes this reaction?
  3. The reaction is directed against what type of recipient Ags?
  4. What type of pt’s is this often seen in?
  5. Acute of Chronic GVHD has epithelial cell death in skin, liver, and GI? What would be the common clinical manifestations seen in this type?
  6. What type of apoptosis occurs with GVH?
A
  1. Solid grafts –> BM, small bowel, lung or liver –> bc these naturally contain # of T cells
  2. Grafted mature T cells in tissue transplant w/ allo-Ags of host
  3. minor histocompatibility Ags (miHAs) of recipient
  4. Immunocompromised
  5. Acute –> rash, jaundice, diarrhea, GI hemorrhage

Chronic –> fibrosis and atrophy of affected organ

  1. FasL (on CTL) and Fas (on recipient DC) and granzyme mediated
24
Q
  1. Immunosuppressive drugs are used for what?
  2. What are the 2 primary goals?
  3. Patients on immunosuppressive drugs are more prone to ______ _____ and have raised incidence of ______.
A
  1. prevention and tx of rejection after transplate
  2. Cnrtl IR against graft Ags and minimize drug’s side effects
  3. opportunistic infections; malignancy
25
Q
  1. What is the MOA for steroids?
  2. What is the MOA for Cyclosporine A?
  3. What is the MOA for Anti-CD3 mAb OKT 3?
  4. What is the MOA for Tarcolimus?
  5. What is the MOA for Anti-CD25 mAb?
  6. What is the MOA for CTLA4-Ig fusion prtn?
A
  1. Anti-inflammatory (via inactivation of NF-κB--> no activaiton of IL-2 and other pro-inflammatory genes)
  2. Inhibits IL-2 gene transcription (block activation of NFAT –> no activaiton of IL-2 and other pro-inflammatory genes)
  3. Inhibits T cell activation and depletion (block signaling of TCR –> 1st signal)
  4. Inhibits IL-2 gene transcription (block activation of NFAT –> no activaiton of IL-2 and other pro-inflammatory genes)
  5. Inhinits IL-2R signaling (CD25 = IL-2 α receptor, so blocking the 3rd signal)
  6. Inhibition of 2nd signal of T cell activation (mediated by CD28:CD80/86)
26
Q
  1. What is the first line of defense tx of transplant rejection?
  2. What is the general mechanism of glucocorticoids?
A

1. Corticosterioids

  • prednisolone (cortisol) and methylprednisolone = anti-inflammatory glucocorticoids
  • transcriptional inhibition of pro-inflammatory genes –> inhibits T cell proliferation –> induction of T cell apoptosis
  1. Inhibition of inflammation
  • low [steroid] –> DNA-dependent regulaiton –> production of IκB inhibitor and IL-10 to induce anti-inflammatory proteins –> dec. inflammation
  • high [steroid] –> block activation of NFκB –> no pro-inflammatory cytokines produced
27
Q
  1. What drug is effective in prophylaxis and tx of allograft rejection in all types of SOLID ORGAN TRANSPLANTS?
  2. Its used as induction therapy and tx of acute or _____ resistant rejection.
A
  1. Anti-CD3 mAB –> OKT 3
  • its an anti-CD3 mouse IgG2a mAB
  • blocks CD3 signaling of T cells
  1. steroid resistant
    * 2nd line of defense
28
Q

What drug/inhibitor is used for IMMUNOPROPHYLAXIS and is a basic component of immunosuppressive protocols in all organ transplants, that has a side effect of nephrotoxicity (kidney toxicity leading to graft loss) and is isolated from fungus species?

A

Cyclosporine A (CsA)

  • peptide from fungus species
  • inhibits calcium-dependent pathway of T cell activaiton
  • It forms a complex = calmodulin-calcineurin
    • this complex inhibits translocaiton of NFAT into nucleus (which is impt for T cell induction)
  • inhibits production of cytokines IL-2, 3, 4, 5, IFN-γ, TNF-α, and GM-CSF

**prevents activation of T cells***

29
Q

What drug is used in all types of organ transplants for maintenance immunoprophylaxis and tx of actue rejection, that has a side effect of nephrotoxicity (kidney toxicity leading to graft loss) and is isolated from Steptomyces ssp. species?

A

Tacrolimus = macrolide lactone

  • simialr to CsA –> as it inhibits Ca+2-dependent pathway of T cell activation
    • forms a complex that inhibits translocation of NFAT to the nucleus
    • inhibiting IL-2, 3, 4, 5, IFN-γ, TNF-α, and GM-CSF
    • **prevents activation of T cells***
30
Q

What drug prevents interaction of CD28 w/ CD80/86 inhibiting the second signal of T cell activation?

A

CTLA4-Ig Fusion Prtn

  • only signal 1 is received
  • no activaiton of T cell –> apoptosis and anergy

Immunology Exam 3 (6 decks)

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