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Transplant Immunology
#1
This is post no. 1 under the main topic.
Transplantation refers to the act of transferring cells, tissues, or organs from one site to another.

Types :
1. Autograft is self-tissue transferred from one body site to another in the same individual.(Transferring skin, blood vessels)
2. Isograft is tissue transferred between genetically identical individuals.(Between two genetically identical (monozygotic) twins).
3. Allograft is tissue transferred between genetically different members of the same species.(Organs transferred from one individual to another unless)
4. Xenograft is tissue transferred between different species.(Graft of a baboon heart into a human)

Autografts and isografts are usually accepted, owing to the genetic identity between graft and host. Allograft rejection can occur in 2 sets due to Specificity & Memory.

- First set reject : (Tissue transferred from inbred mouse Strain A to Strain B)When graft is transplanted for the first time. Complete Rejection can occur by 12-14 days.

- Second set rejection : Graft rejection reaction develops more quickly, with complete rejection occurring within 5-6 days. Equivalent to grafting between Strain C and Strain B.

T-cells play an important role in Allograft rejection. Nude mice(which lack Thymus, thus lack functional T cells) were found incapable of allograft rejection. Removal of CD8⁺ population did not have effect in increasing rejection time(15 days control mouse), removal of CD4⁺ prolonged survival to 30 days, while removal of both increased survival of allografts upto 60 days.

Tissue with antigenic similarity Histocompatible; tissues displaying significant antigenic differences are histo-incompatible and induce and immune response leading to tissue rejection. Out of 40 loci responsible for allograft rejection is most vigorous. MHC Organization in mice – H-2 complex, HLA complex in humans. MHC loci are inherited as a complete set called a Haplotype from each parent. Therefore the F1 generation can accept allografts from the parents but the vice versa is not possible because the parents have only 1 halotype each, unlike the offsprings that have both.

Graft compatibility can be judged by screening ABO blood group compatibility, followed by HLA typing.

Cell mediated graft rejection occurs in 2 stages : 1. Sensitization , 2.Effector Stage.

1. Sensitization Phase:
During the sensitization phase, CD4+ and CD8+ T cells recognize alloantigens expressed on cells of the foreign graft and proliferate in response. Both major and minor histocompatibility alloantigens can be recognized. In general, the response to minor histocompatibility antigens is weak, although the combined response to several minor differences can sometimes be quite vigorous.The response to major histocompatibility antigens involves recognition of both the donor MHC molecule and an associated peptide ligand in the cleft of the MHC molecule.

- A host TH cell becomes activated when it interacts with an antigen-presenting cell (APC) that both expresses an appropriate antigenic ligand–MHC molecule complex and provides the requisite co-stimulatory signal. Depending upon the tissue, different populations of cells within a graft may function as APC (Majorly dendritic cells as they are found in most tissues and they express high levels of Class II MHC molecules).

- APCs of recipient can also migrate into a graft and endocytose the foreign alloantigens and present them as processed peptides together with self-MHC molecules.

- In some grafts, a population of Donor APCs called passenger leukocytes migrate from graft to regional lymph nodes. They are dendritic cells with high levels of Class II MHC molecules along with normal levels of Class I MHC molecules. They are recognized as foreign and can stimulate an immune activation of T lymphocytes in the lymph node.


2. Effector Phase:
- It involves delayed hypersensitivity and CTL mediated cytotoxicity.
- There is an influx of T cells and macrophages into the graft, histologically resembling the Delayed type hypersensitive response, in which cytokines produced by TDTH cells promote macrophage infiltration. Recognition of foreign Class I alloantigens on the graft by host CD8⁺ cells can lead to CTL- mediated killing. In some cases CD4⁺ T cells mediate graft rejection.
- In each effector mechanism, cytokines secreted by TH cells play a central role.

- IL-2, IFN-_, and TNF-_ have each been shown to be important mediators of graft rejection.

Hyper-acute Rejection :
- Cases in which the grafted tissue never becomes vascularized.
- Caused by pre-existing host serum antibodies specific for antigens of the graft.
- Occurs if there is ABO blood type mismatch.
- The antigen-antibody complexes formed activate the complement system, resulting in intense infiltration of neutrophils into the grafted tissue, causing an inflammatory response, leading to clotting of blood in the bloodvessels, preventing vascularization of the graft.
- found in individuals with multiple blood transfusions/ multiple pregnancies.

Acute rejection :
- Cell mediated rejection manifests as an acute rejection of the graft beginning about 10 days after transplantation.
- Occurs due to massive infiltration of macrophages and lymphocytes at the site of destruction, suggesting T(H) cell activation and proliferation.

Chronic Rejection :
- Develops after months or years after acute rejection reactions have subsided.
- Include both humoral and cell-mediated responses by the recipient.
- Immunosuppressive drugs can be used to prolong the duration of survival, although difficult conditions may need another transplantation.

Immuno Suppressive Drugs :

MITOTIC INHIBITORS
1. Azathioprine
- A potent mitotic inhibitor, given just before & after transplantation to diminish Tcell proliferation in response to the alloantigens of the graft.
- Acts on cells in the S phase, blocks synthesis of inosinic acid, which is a precursor for purine synthesis.
2. Cyclophosphamide
- Is an alkylating agent, that inserts into the DNA helix and becomes cross linked, leading to disruption of the DNA chain.
- Especially effective against rapidly dividing cells and therefore given at times of grafting to block T cell proliferation.
3. Methotrexate
- Acts as folic acid antagonist and blocks purine biosynthesis.



CORTICOSTEROIDS

- Corticosteroids, such as prednisone and dexamethasone, are potent anti-inflammatory agents that exert effects at many levels of the immune response.
- These drugs are often given to transplant recipients together with a mitotic inhibitor such as Azathioprine to prevent acute graft rejection.

FUNGAL METABOLITIES

- Cyclosporin A (CsA) & FK506 although chemically unrelated, have similar functions and both block activation of resting T cells.
- Rampamycin prevents expression of IL2, IL2R.

SPECIFIC THERAPY
- Monoclonal antibodies directed against various surface molecules on cells of the immune system have been used successfully to suppress T-cell activity in general or suppress the activity of sub-populations of T cells.
- Monoclonal antibodies can be used to deplete the recipient of a certain broad or specific cell population, therefore blocking co-stimulatory signals. In a later stage a state of anergy is induced in those T cells that react to antigens present on the allograft.
- A strategy involves use of monoclonal antibodies to the CD3 molecule of the TCR complex. Injection with such antibodies results in depletion of mature T cells from the circulation, which is caused by binding of antibody-coates T cells to Fc receptors on phagocytic cells, which then phagocytose and clear T cells. A similar strategy involes monoclonal antibodies against high affinity IL-2 receptor.
- Another target of monoclonal antibodies are cell-surface adhesion molecules.

CO-STIMULATORY MOLECULES:
- CD28 or CTLA-4 molecule present on T cells & B7 molecule present on APCs provide co-stimulatory signals for T cell activation.
- CD28 is expressed on both activated and inactivated T cells.
- CD28 binds with B7 with moderately affinity but binds with CTLA-4 with 20 fold higher affinity.
- B7 and CTLA-4 both have Antibodies and thus can bind to CD28.
- When CTLA-4 + CD28 = No T cell activation.
- But when B7 + CD28 = T cell activation.

ACCEPTANCE OF ALLOGRAFT

1. When cells or tissue are grafted from privileged site (include anterior chamber of the eye, the cornea, the uterus, the testes and the brain) that has been sequestered from immune-system surveillance.

2. When a state of tolerance has been induced biologically. It occurs by a previous exposure to the antigens of the donor in such a manner that it led to development of immune tolerance rather than sensitization in the recipient.
 
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