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I & I Part I > Transplant Immunity > Flashcards

Transplant Immunity Flashcards

1
Q

Autologous graft (autograft)

A

self graft

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2
Q

Isograft, homograft, syngeneic graft

A

a graft from one genetically identical individual to another (e.g. identical twins)

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3
Q

Allograft

A

a tissue graft from a donor of the same species as the recipient but not genetically identical

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4
Q

Xenograft

A

a graft from a different species (e.g., from monkey to man)

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5
Q

Histocompatible

A

sharing identical histocompatibility (tissue typing) antigens (i.e., HLA)

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6
Q

The Immunology of Graft Rejection

A
  • Primarily due to T cell mediated cytotoxicity.
  • The graft has MHC class I molecules on its membranes which is antigenically and immunologically different from the host MHC class I; cytotoxic T cells (CD8+ CTL) respond to and participate in destruction of the graft.
  • Lymphoid cells and APC in the graft also express foreign MHC class II molecules, which activates CD4+ helper T cells which expands the immune response to include not only CTL but other effector cells (e.g. macrophages and NK cells).
  • The helper T cells help activate cytotoxic cells, which then kill the graft cells.
  • Graft rejection can also result from differences in what are referred to as minor (i.e. non-HLA-A, B, DR) histocompatibility antigens.
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7
Q

Other parts of the immune response also facilitate graft rejection

A
  • Surface Ig on B cells can bind the foreign MHC molecules, and with T cell help, make Abs.
  • Abs can kill in combination with complement (complement-mediated cytotoxicity) or once bound on the surface of macrophages or killer cells (ADCC).
  • Macrophages activated by T cells and by Ab/complement opsonization can kill and engulf the graft cells.
  • Natural killer (NK) cells activated by T cell cytokines may also kill the graft directly and/or can also release cytotoxic cytokines (e.g. TNF-alpha).
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8
Q

HLA Class I Alleles:

A

present on all nucleated cells and platelets

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9
Q

HLA Class II Alleles:

A

generally restricted to APC (B, monocytes, DC) & activated T cells

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10
Q

HLA Linkage Disequilibrium:

A

when HLA loci/alleles occur at unexpected frequencies

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11
Q

Genetics/Inheritance of HLA Antigens

A
  • Each individual inherits a package (i.e., called a haplotype, found on one chromosome) of MHC genes from each parent.
  • Unless the parents share MHC haplotypes, children will not completely match either parent (i.e., they will be haploidentical).
  • Children have a 1 in 4 chance of perfect matching to their siblings (Mendelian inheritance).
  • A 12 of 12 match (i.e., at both alleles for HLA-A, B, C, DR, DP and DQ) is ideal. However, in many cases a 6 of 6 match (HLA-A, B, DR) will suffice (because C is less variable and DP and DQ exhibit linkage disequilibrium).
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12
Q

Relative Importance of Histocompatibility Antigens in Graft Rejection

A
  • MHC class II: are the most (but not the only) important molecules (especially HLA-DR); because it activates helper T cells
  • MHC class I: very important (especially HLA-A and B); because it induces Abs and activation of CTL.
  • Minor histocompatibility antigens induce weaker graft rejections than major MHC antigens, but can cause rejection (especially if multiple minor antigens are mismatched). Normal proteins that are polymorphic in a given population and presented by MHC.
  • Blood type antigens: same problem as with transfusion reactions (due to natural Abs); these antigens are found on surface of blood vessels (endothelial) cells.
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13
Q

Solid Organ Graft:

A

e.g. the graft is a tissue like a kidney or liver; the recipient is immunocompetent; danger of donor organ rejection by the recipient.

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14
Q

Stem Cell Transplants:

A

e.g. the graft is a bone marrow collection; recipient is immuno- incompetent; the donor graft rejects (attacks) the recipient

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15
Q

Discrepancies in either MHC class I or II antigens at any of the loci will result in…

A

…an immunological reaction leading to graft rejection (for organs) or graft-versus-host disease (GVHD, for stem cell transplants).

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16
Q

Types of Graft Rejection - Hyperacute

A

very fast (minutes to hours); due to preformed cytotoxic Abs (type II); cannot be stopped except by removal of graft, results in graft ischemia & necrosis

17
Q

Types of Graft Rejection - Acute

A

begins within 7-10 days due to HLA mismatch but up to 21 days for minor mismatches; due to CMI +/- Ab; development of an allogeneic reaction; may be stopped with immunosuppressant therapy

18
Q

Types of Graft Rejection - Chronic

A

begins after 3 months (by definition); due to disruption of graft tolerance; CMI +/Ab; damage to tissue cannot generally be reversed with immunosuppression; generally irreversible

19
Q

Clinical Suppression of Graft Rejection - Anti-Inflammatory Drugs

A

e.g. steroids which block inflammatory tissue destruction by most immune cells

20
Q

Clinical Suppression of Graft Rejection - Anti-metabolites

A

block cell division of activated T cells (mycophenelate mofetil, azathioprine)

21
Q

Clinical Suppression of Graft Rejection - Cytotoxic Agents

A

kill Iymphocytes (e.g. anti-lymphocyte serum; ATG; steroids; alkylating agents, antibiotics; irradiation).

22
Q

Clinical Suppression of Graft Rejection - Cyclosporin A

A

or similar reagents that suppress IL2 production or use by helper T cells (FK506/Tacrolimus, rapamycin/Sirolimus).

23
Q

Clinical Suppression of Graft Rejection - Enhancing Abs

A

block tissue recognition or response by T cells (CTLA4-Ig, anti-CD3/Muromonab; anti-IL2R [Daclizumab, Basillximab]).

24
Q

Clinical Suppression of Graft Rejection - Mycophenolate mofetil

A

inhibits purine synthesis in T and B cells and their proliferation.

25
Q

Bone Marrow/Stem Cell Transplantation and Graft versus Host (GVH) Reactions

A
  • Bone marrow, due to the method of harvest, contains Iymphoid progenitor cells as well as large numbers of mature Iymphocytes which can mature/be activated in the new host and mount a GVH immune response leading to GVH disease (GVHD). GVHD affects skin, spleen, liver & gut (highly proliferative tissues).
  • Bone marrow recipients are immuno-incompetent recipients who cannot react against the graft. However, the graft can react against the recipient.
26
Q

GVHD and Bone Marrow Transplantation:There are three major differences from other types of transplants.

A

1) Because the graft is immunocompetent, if it reacts against the recipient, graft vs. host disease (GVHD) can become a major problem.
2) Because of massive doses of pre-transplant immunosuppression (e.g. radiation and steroids), acute rejection of the stem cell graft is a relatively uncommon problem.
3) As a result of immune dysfunction, the most common underlying condition for which transplants are performed, cancer, remains a threat to return (i.e. relapse due to residual disease).

27
Q

Bone Marrow Transplant Procedure

A
  1. Identify a histocompatible donor
  2. Initiate Preparative Therapy
    - A combination of chemotherapy and radiotherapy, in which one also ablates the marrow and the immune system as a consequence of attempting to destroy the underlying hematological condition.
  3. Marrow/Stem Cells Are Infused Intravenously
28
Q

Early complications after stem cell transplant

A

1) Tissue injury from the chemotherapy (gut, liver, lung; highly proliferative tissues are most susceptible)
2) Neutropenia/marrow aplasia (platelets, RBC, risk of infections) from the preparative therapy, and
3) the Immune deficiency (increased infection risk and risk of relapse) that may last for months to years until immune system is reconstituted.

29
Q

Late complications after stem cell transplant

A
  • Graft vs. host disease (GVHD) occurs 20-70% of the time.
  • Relapse from residual malignant disease not removed by preparative therapy can occur.
  • Infection due to aplasia and immune dysfunction
30
Q

The Immunology of GVHD

A
  • Occurs in opposite direction of organ rejection
  • Immune cells from graft react against host
  • Acute and chronic forms are based on time
  • Abrogated by the development of tolerance (eventually)
31
Q

How Does GVHD Arise during BMT?

A
  • Cytoreductive conditioning is thought to induce tissue damage and release of proinflammatory cytokines that activate APC and prime donor T cells.
  • T cell activation through APC co-stimulation then occurs.

– Produces a highly skewed TCR repertoire

– Induces a loss of self-tolerance

  • Alloreactive T cell expansion and differentiation then occur.
  • Activated T cells traffic to GVHD targets such as gut, liver, skin and lung (as well as recruitment of other effector cells once there).
  • Destruction of target tissues then ensues.
  • It is generally not feasible to prevent GVHD by T cell depletion of the graft in that it results in increased risks of graft failure and malignant relapse.
32
Q

Acute GVHD

A
  • First 100 days after transplant (by definition)
  • Usually starts around the time of immune engraftment
  • Diarrhea, jaundice, erythematous rash are characteristic
  • Platelet consumption due to tissue damage and immune reactions can be very high
  • Immune deficiency and dysfunction are produced
33
Q

Chronic GVHD

A
  • Beyond 100 days (by definition)
  • Anorexia (using due to production of cachexia cytokines)
  • Scaly skin rash (similar to connective tissue autoimmune disease, fibrosis & sclerosis)
  • Dry mouth, dry eyes (mucosal membrane damage)
  • Liver dysfunction (hepatitis)
  • Primarily due to Th17 &Tc17 (it seems) with abnormal Treg cells

– Responsive to pirfenidone (anti-fibrotic)

  • Primary characteristic is fibrosis and semblance to autoimmune dx
34
Q

Treatment of GVHD (and rejection)

A
  • Cyclosporine/tacrolimus
  • Sirolimus (rapamycin; anti-mTOR)
  • Steroids
  • Mycophenolate
  • Monoclonal antibodies (anti-CD3, CTLA4-Ig, anti-IL2R)
  • Anti-thymocyte globulin

NOTE: Unlike rejection in solid organ transplantation, GVHD and the risk for it are almost always temporary - almost all patients eventually (6 months to years) can terminate immunosuppression, if they survive.

35
Q

Solid Organ

A

The recipient will reject the donor: Nothing about the donor can be foreign to the recipient

36
Q

Bone Marrow

A

The donor will reject the recipient: Nothing about the recipient can be foreign to the donor

I & I Part I (25 decks)

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