Intro to Transplantation 9/12

Question 1

Syngeneic, Allogenic, Xenogeneic, Minor Histocompatability Antigen

Answer 1

• Syngeneic- transplantation between genetically identical individuals
• Allogeneic- transplantation between genetically dissimilar individuals of the same species
• Xenogeneic- transplantation between different species
• Minor histocompatibility antigen- normal proteins on the cell surface that are polymporphic in nature

Question 2

Evidence for role of MHC in mouse grafts

Answer 2

Other evidence for the role of MHC in transplant rejection:

• Cells or organs transplanted between genetically identical individuals are not rejected
• Cells or organs transplanted between genetically nonidentical individuals are rejected

In panel 1: syngeniec transplantation – no rejection
In panel B – mice have different HLA type, and results in rejection
Panel C: MHC a/b mouse can have a graft from MHCb
Panel D: MHCa/b can’t give a graft to MHCa

Question 3

Direct alloantigen recognition vs. indirect alloantigen presentation

Answer 3

1) direct alloantigen recogntion

• allogenic APC in graft has an allogeneic HLA. The t cell recognizes the unprocessed allogeneic HLA molecule on graft APC and results in alloreactive T cell.
• normally CTL’s are alloreactive cell
• most likely seen more in actue rejection
• CD8+ T cells

2) indirect alloantigen presentation:

• Allogenic HLA is recognized on the donor tissue by the recipients APC. Recipient APC uptakes and processes the allogeneic HLA molecules and presents the peptide of the allogenic HLA molecule bound to self HLA molecule to an alloreactive T cell. (most likely CD4+)
• normally CD4T cells are alloreactive cell
• Alloreactive B cells can also be stimulated to produce alloAbs in the indirect presentation pathway
• most likely seen in chronic rejection

Question 4

Direct presentation of HLA Alloantigens

Answer 4

1. ) Normally Self HLA molecules present foreign peptide to T cell selected to recognize self HLA weakly (positive selection), but may recognize self HLA- foreign peptide complexes as well
2. ) Allorecognition:

• the self HLA-restricted T cell recognizes the allogeneic HLA molecule whose structure resembles a self HLA foreign peptide complex
• The self HLA-restricted T cell recognizes a structure formed by both the allogeneic HLA molecule and the bound peptide

It is possible that 1-2% of all T cells will recognize a single allogeneic MHC. The high probability that T cells will recognize foreign MHC proteins is due to:

• T cells are selected to have low affinity for MHC molecules (positive selection). In addition, T cells with high affinity for allogeneic MHC molecules are not negatively selected for and therefore may exist.
• Due to structural similarities, self MHC-restricted T cells are able to recognize foreign MHC molecules.
• The allogeneic MHC with bound peptide may mimic a self MHC and peptide complex.

In allorecognition the structure of allongeneic MHC fits the TCR

Question 5

Costimulation is required to generate a T cell response to an allograft - what events would trigger for costimulation expression in transplantation patients?

Answer 5

• inflammation or presentation of danger signals/recognition of foreign signals results in the CD28/B7 sencond signal.
• blocking the costimulation is a mechanism of blocking graft rejection

Question 6

Hyperacute Rejection

Answer 6

• Response occurs within minutes to hours after transplantation
• Characterized by thrombosis of graft vessels followed by ischemic necrosis (clotting within the transplanted tissue)
• Mechanism
• Host circulating antibodies are specific for antigens on graft endothelial cells (usually IgG)
• Complement activation leads to endothelial cell injury
• Inflammation, thrombosis and vascular occlusion occurs
• result of immune system responding to a mismatch of some sort - i.e. blood group mismatch. Can be largely preventable by cross-typing

Question 7

Acute Rejection

Answer 7

Responses occur within days to weeks after transplantation

• Acute rejection is stimulated by alloantigens in the graft
• Mechanisms of rejection
• Acute cellular rejection (both CTL and CD4 activated - stimulates macrophages and killing of graft tissue)- microvascular endothelialitis is a frequent early finding
• Acute antibody-mediated rejection- characterized by transmural necrosis of graft vessel walls
• endothelialitis (inflamation around endothelial cells)
• less preventable than hyperacute rejection- but it is treatable

Question 8

Chronic Rejection

Answer 8

Responses occur months to years after transplantation

Mechanism

• T cells and antibodies react against alloantigens
• The immune response results in fibrosis of graft tissue and gradual narrowing of vessels (graft arteriosclerosis)
• Chronic rejection is refractory: results in fibrosis- where vessels are narrowed. This is unable to be treated.

Question 9

Anti-TCR (Thymoglobulin, OKT3)

Answer 9

Interferes with T cell activation and effector function

blocks signaling through TCR by binding the TCR CD3 receptor and inhibiting production of IL2

Question 10

CTLA4-Ig

Answer 10

Binds to B7 and blocks the costimulation with CD28, thus preventing IL-2 production - Immunosuppresses T cells

Question 11

Cyclosporine, FK506

Answer 11

Interferes with T cell activation and effector function

blocks production of calcinuerin, and no IL-2 production following the binding with TCR

• since its introduction, the survival rate of allograft transplant survival has greatly increased

Question 12

Anti-IL-2R

Answer 12

Interferes with T cell activation and effector function by blocking IL-2R on the T cell, and results in lack of T cell proliferation

Question 13

Rapamycin and Azathioprin and Mycophenolate Mofetil

Answer 13

Interferes with T cell activation and effector function by inhibiting the signaling following reception of IL-2 in the IL-2R. Resulting in lack of T cell proliferation

Question 14

3 side effects of Immunosuppression

Answer 14

1. Malignancy: T cells have ability to eliminate tumor cells that have formed – if you prevent T cell actions, then you have higher risk of cancer. T cells eliminate transformed cells.
2. Infections: people who are chronically immunosuppressed would be more prone to infections because you are dampening the T cell effects
3. Drug toxicity: Cyclosporin has toxic effects on kidneys.

Question 15

Non-T Cell targets for immunosuppression

Answer 15

• Drugs targeting alloantibodies and alloreactive B cells
• Anti-inflammatory drugs
• Inhibitors of leukocyte migration

Question 16

Strategies to Minimize Alloantigenic Differences

Answer 16

• ABO blood group antigens are selected to be compatible between the donor and recipient
• Matching of HLA alleles between the donor and recipient
• Testing for preformed antibodies against donor HLA (crossmatching test)

Question 17

Induction of Donor-Specific Tolerance

Answer 17

• Costimulatory blockage
• Hematopoietic chimerism: recipient will be tolerant to both their own tissues and donor tissues
• Transfer of regulatory T cells

Question 18

ABO Blood Group Ags

Answer 18

Type A: have anti-B Abs. A Ag is present on cells

Type B: have anti-A Abs. B Ag is present on cells

Type AB: no Abs present. A/B Ag is present on cells

• universal recipient

Type O: have anti-A and anti-B Abs. No Ag is present on cells

• universal donor

A Ag: has extra N-Acetyl-galactosamine

B Ag: has extra Galactose

Why do people without A and B antigens develop anti-A and anti-B antibodies?

It is believed that antibodies arise in response to normal gut flora which contain antigenic epitopes that are similar to A and B blood-group antigens. People with A and B blood type are tolerant to these antigens; however, people with blood type O do not have exposure to these antigens during development and therefore will develop anti-A and anti-B antibodies.

Question 19

Other Blood Group Ags: Lewis, Rhesus (Rh)

Answer 19

Lewis Antigen

• Fucosylation at additional terminal sites of the blood group antigen

Rhesus (Rh) Antigen

• Nonglycosylated, hydrophobic cell surface proteins
• 15% of the population has a deletion or other alteration in the RhD allele (Rh negative)

Question 20

Hematopoietic Stem Cell Transplantation

Answer 20

• Hematopoietic stem cell transplantation is the transfer of allogeneic pluripotent hematopoietic stem cells (from bone marrow) to a recipient. The recipient is treated with irradiation beforehand to deplete bone marrow and make room for the transferred cells. The allogeneic cells should repopulate the recipient with all hematopoietic lineages.
• This is the transplantation of bone marrow – used for inherited immunodeficiencies (such as loss of reg T cells)

Question 21

Graft-Versus-Host-Disease (GVHD)

Answer 21

• Reaction of mature grafted T cells to alloantigens of the host
• Usually directed against minor histocompatibility antigens
• Acute (<100 days)- epithelial cell death in the skin, liver, and gastrointestinal tract (one of first symptoms is rash on face)
• Chronic (>100 days)- characterized by fibrosis and atrophy without acute cell death
• Treated by immunosuppression- which target the donor lymphocytes
• Protocols that deplete mature T cells from the donor cells can prevent GVHD; however, there are drawbacks. Mature T cells are needed in the treatment of leukemias, therefore the graft versus leukemia effect is lost in the absence of T cells. Mature T cells also appear to help engraft new bone marrow cells.
• A Complication in graft vs. host disease: usually directed against HLA

Question 22

summary slide

Answer 22

• The immune system targets foreign tissue for rejection. The major antigenic targets are MHC molecules.
• Graft antigens can be presented directly to T cells or by host APC’s (indirect).
• The mechanisms of graft rejection include hyperacute, acute, and chronic rejection. All have specific mechanisms.
• Treatment for graft rejection relies primarily on immunosuppression.
• Bone marrow transplants present a risk for graft-versus-host disease and often result in temporary immunodeficiency in recipients.