TRANSPLANTATION

 

  TRANSPLANTATION

´ Reason for transplantation is to re-establish a function lost following:

´ physical loss  or end-stage disease or of a given organ or tissue

´ Accident

´ Sickness

Some terms

´ 1.  Xenograft –a transplant between members of different species e.g. human and mice

´ 2. Autograft – whereby a tissue or organ is transplanted within the same individual, in clinical practise, the tissues is transplanted to a new site

´ 3.Allograft – a graft between genetically non-identical members of the same species-namely invariable rejection - common

´ 4. Syngraft – a graft between genetically identical subjects e.g. monozygotic twins, would not undergo rejection.

´ Rejection can be controlled by drastically restraining the immune system---immunosuppression

´ Genetically different individuals are not histocompatible i.e. reject each others tissues, the incompatibility is due to MHC glycoproteins



Transplanting a segment of skin from mouse A into the genetically unrelated mouse B (allotrasplantation), the skin is rejected in 7-14 days---primary rejection

If mouse B is transplanted again with skin of mouse A, the rejection occurs more speedily-secondary rejection

 

Mechanism of rejection

´ Tissues of rejecting organs obtained by biopsy were analysed

´ It contained inflammatory infiltrate composed of nuclear white blood cells ( lymphocytes and macrophages)

´ On analysis of the inflammatory infiltrate with monoclonal antibodies, it showed heterogeneous components i..e. CD4 cells, CD8 cells, macrophages, B-lymphocytes and natural killer cell

´ Therefore there is evidence to suggest that mechanism prevailing during physiological immune response also apply to graft    rejection.

Mechanism of rejection



´ Once a naïve Helper T-cell has recognized an alloantigen, presented by an APC (Dendritic cell)

´ If the surrounding media is rich in IL-2, IFN-y the T-helper cell will commit itself to the activation of  CTL & NKC

´  MQ is activated through release of TNF-β and IFN-y

´ IFN-y recruits and activates macrophages, enhance MHC expression on the graft, making the graft susceptible to the cytotoxic action of CD8 cells

´ IL-2 –activates CTL cells

´ IF the prevailing environment is IL-2,4,5 and IL-6, the T-helper, directs activation of B-lymphocytes and antibody production

´ Antibodies enhance graft rejection through complement and by activation of NKC through ADCC

 

ALLOANTIGEN RECOGNITION

´ How does the host recognize the alloantigens?

´ This can be done in 2 ways

the recipient immune system could recognize an intact MHC molecule (donor  - peptide and MHC)(Direct allorecognition)

2. Peptide from the donor derived from foreign MHC molecule could be presented within the groove of the recipient MHC molecule indirectly (Indirect allorecognition) (peptide—donor, MHC –recipient)

Recognition of intact MHC molecule, outnumbers recognition of processed alloantigens: This is because

The alloantigens recognised by the recipient immune system consists of MHC molecule  and peptides generated within the donor before transplantation

´ These carry over peptides provide extra alloantigenic stimuli

3. Empty donor MHC molecules have been shown to provide a poor allogeneic stimulus

 

CLASSIFICATION OF REJECTION REACTIONS

1.    Hyperacute rejection

2.    Acute rejection

3.    Accelerated acute rejection

4.    Chronic rejection

a)    Hyperacute rejection

´ Mediated by pre-formed antibodies in the recipient against the donor organ.

´ It occurs within minutes to a few hours after transplantation e.g ABO blood group barrier

´ Other than antibodies, hyperacute rejection is characterised by complement and heavy polymorphonuclear leukocyte infiltration

´ Example when an organ from group A or B is transplanted into a O recipient, whose circulation contain anti-A or anti-B.

ABO blood group



People who are AB+ are universal recipients, (can receive a blood transfusion of any other blood type)

.  O- individuals are universal donors, (their blood can be given to people of any blood type)

b)    Acute rejection

´ Mediated by T-lymphocytes

´ Occurs some 7 days post-transplantation

´ Recipients T-cells recognize alloantigens mainly through direct allorecognition –(Donor MHC loaded with carry over peptides are recognized by recipients immune system).

´ Has lymphocyte and monocyte-rich cell infiltration

c)    Accelerated Acute

´ An accelerated form of acute rejection that occurs within 1-5 days post-transplant is mediated by T-lymphocytes that have been previously sensitised to alloantigens  through transfusion and pregnancies

d)    CHRONIC REJECTION

´ Occurs months or years after successful transplantation

´ Major cause of long-term graft loss

´ Caused by damage to the endothelium, this can be damaged by antibodies to alloantigens, deposition of immune complexes, activation of complement, activation of clotting cascade

´ This favours endothelial cell proliferation and narrowing of vascular lumen

´ MQ activate cytokines (IL-1,IL-6, & TNF)

´ Adhesion molecules are up-regulated on endothelial cells

Immunosuppressive Therapy

1. Corticosteroids: have multiple effects on the immune system e.g. decrease the  number of circulating B-lymphocytes and inhibit:

´ monocyte trafficking

´ Reduce T-cell proliferation

´ Reduce cytokine gene expression ( i.e. transcription of IL-1, IL-2, IL-6, IFN-γ and TNF-α

´ Side effects of these drugs on skin, bones and other tissues is still a problem in clinical transplantation.

2. Cyclosporin A

Is a small fungal cyclic peptide, it is NB  in clinical transplantation since early 1980s

Action

´ Effect on T-cell is through inhibition of IL-2 secretion

´ Stimulation of production of cell growth-inhibitory cytokines such as transforming growth factor (TGF-B). TGF is released by TH cells, MQ, monocytes

´ TGF-B inhibits T-cell proliferation

´ Inhibits generation of cytotoxic lymphocyte

´ Side effects
Nephrotoxicity-dose dependent and reversible

3. Tacrolimus

´ A macrolide antibiotic isolated from Japanese soil fungus Streptomyces tsukubaensis (action like cyclosporin A)

4. Sirolimus (rapamycin)-a macrolide, mode of action similar toTacrolimus and Cyslosporin A.

 

Reference

Hussain Y, Khan H. Immunosuppressive Drugs. Encyclopedia of Infection and Immunity. 2022:726–40. doi: 10.1016/B978-0-12-818731-9.00068-9. Epub 2022 Apr 8. PMCID: PMC8987166.

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