Transplant Immunology Flashcards
Syngeneic
Allogeneic
Alloantigens
Syngeneic: Genetically Identical animals; Identical grafts
Allogeneic: Genetically Different animals; Different grafts
Alloantigens: Antigens that are the Target of Rejection
Autografts
= Tissue transplanted from one part of the Body to another in Same Person.
Examples:
-*Skin Grafting of intact skin to an area of a burn injury.
-*Autologous Bone Marrow Stem Cell Transplant.
Advantage: *No Risk for Rejection
Allografts
= Tissue transplanted in Same Species, from one human to another.
Examples:
-Transplantation for Most Organs, such as Kidney, Heart, Liver, and Lung.
-*Blood Transfusion
(temporary because the finite lifespan of transfused blood cells)
Risk of Rejection is a significant problem.
Xenografts
= Tissue is transplanted from One Species to Another Species
Example: *Pig Heart Valves to replace damaged human heart valve.
High risk of rejection and thus whole organ transplants are rare with this method.
Allograft Antigens
Are the main targets for rejection.
Are MHC molecules. = *HLA complex in humans.
Humans express *6 Class I alleles (2 A, 2 B, and 2C) and *6-8 Class II alleles (2 DP, 2DQ, 2-4 DR)
*A, B, DQ, and DR are Very Polymorphic. –Most important ones.
These alleles are *Inherited and *Expressed in Various Combinations.
–*Each person expresses a Unique Combination, which is *Very Likely to Appear Foreign to Another Person (except for identical twins).
All MHC molecules are potential targets for rejection, but the *C and *DP loci play a Minor Role.
*Recognition of Foreign HLA Antigen from another person is *One of the Strongest Immune Responses Known.
Allorecognition
2 Types:
1) The T cell recognizes an Allogenic MHC whose structure resembles the Self MHC-Foreign peptide complex.
- -> That is, the Allogenic MHC is recognized as itself being foreign by the T cell receptor and is able to stimulate the TCR.
2) The T cell recognizes a structure formed by both the Allogenic MHC molecule and the Bound Donor peptide.
- -> Thus, neither is able to stimulate the TCR on their own, but together, they are.
Minor Histocompatibility Antigens
Most of these are Allelic forms of Normal proteins slightly different between Donors and Recipients.
Rejections elicited by these Antigen are not as strong as for the HLA antigen.
However, **These are Important in Blood Transfusions and in Bone Marrow Transplants.
Blood Transfusions
*Antigens on the Surface of RBCs are Minor Histocompatibility Antigens.
Best known: *A and *B Glycoproteins
–> These determine the 4 blood types:
A, B, AB, and O (lack of A and B)
**Antigen Matching is Mandatory before blood transfusions.
ABO antigens are expressed on RBCs, Endothelial cells, and some other cells.
(O are good donors, b/c won’t be rejected. However, they can only receive O blood.)
ABO Molecules are *Glycosphingolipids, which are glycans bound to sphingolipid A (N-acetylgalactosamine), or sphingolipid B (galactose), or both (AB), or None (O).
–Individuals are Immunotolerant to their own ABO antigens, but produce Antibodies against the others.
These preformed Antibodies react against transfused blood cells and can produce severe transfusion reactions.
Tissue Typing
**Successful Transplantation Requires careful HLA Tissue Typing to optimize match between donor and recipient.
Potential for 12-14 separate HLA loci:
- 6 Class 1 (2A, 2B, 2C)
- 6-8 Class 2 (2-4 DR, 2 DQ, 2DP).
However, *Only 6-8 of these have **Major Importance: Alleles A, B, DR
HLA antigens are not expressed uniformly throughout all tissues.
–**Heart and **Liver Don’t Express **Class 1 antigens *in large amounts and are *Less Likely to be Rejected than **Kidney or **Bone Marrow transplants.
–Heart and Liver also contain fewer APC, which are needed for immune activation.
–Thus, determinants for Heart and Liver transplant are availability and organ size, rather than type matching.
Because Immunosuppressive Therapy has become so effective, *HLA typing is not as critical now as it was before.
–Tissue typing is *Not even necessary for *certain types of transplants.
–Recipients may be too sick to wait long time for the closest match and it might be better to assume some risk of rejection otherwise controlled by immunosuppressive therapy.
Hyperacute Rejection
Occurs when there are *Preformed Antibodies Against Transplant *Endothelial Cells in the Recipient,
- -Which immediately attack the Donor kidney and cause *Acute Vascular injury
- **Minutes after Transplantation.
Characterized by *Thrombosis of the Graft Blood Vessels and *Ischemic Necrosis of the Graft.
Preformed Antibody to Blood Group Antigens or Allogeneic HLA are Due to *Prior Exposure during *Blood Transfusions, *Pregnancy, or *Prior Transplantation.
–Antibody bind to Endothelium and Activate Complement and Clotting Systems, leading to Injury.
**Virtually never seen anymore because Tissue Typing is always performed beforehand.
Acute Rejection
Occurs within **Days or Weeks after Transplant.
Is the principal cause of Early Graft Failure.
- Mediated by T cells.
- -Recipient Alloreactive CD8+ T cells recognize Donor antigen presented by Donor cells on Donor MHC.
**Recipient’s CTLs are directed *Against the Graft Parenchyma or *Against Vessels.
- Alloreactive Recipient Antibodies contribute, especially in the *Vascular Form,
- -in which injury is caused mainly by Complement Activation.
(–The Vascular Form is more difficult to treat with immunosuppressive therapy.)
- *Is Often amenable to Immunosuppressive Treatment,
- -particularly directed to block the activation of Alloreactive T cells.
Chronic Rejection
= An **Indolent Form of Rejection
Occurs **Months to Years after Transplant.
*Directed at the *Graft Vessels.
- -Vessels become increasingly *Fibrotic and narrowed, leading to an ischemic injury called
- *Graft Atherosclerosis.
Cytokines secreted by T cells activate proliferation of Fibroblasts and Smooth muscle cells.
–This form of rejection is very hard to treat and has become now the main cause of graft failure.
Cyclosporine
**Most useful drug for treatment of Graft Rejection.
*Allowed for widespread use of Heart, Liver, and Lung Transplantation.
Mechanism:
*Cyclosporine binds to *Calcineurin, a phosphatase activated by Calmodulin, which binds Calcium during Tyrosine Kinase signaling by TCR complex activation.
–Signaling activates downstream Nuclear Factor of Activated T cells **NFAT, leading to production of Cytokines, promoting T cell Activation.
–Thus, Blocking NFAT blocks T cell Activation.
FK 506
*Is a Macrolide Antibiotic that Inhibits T cell Activation.
Corticosteroids
Deplete Lymphocytes.
