Monday Article #31: Organ Transplantation

Organ Transplantation: Achieving the Balance Between Graft Rejection and Immunosuppression

Organ transplantation has become a life-saving procedure to treat patients with irreversible end-stage organ failure such as lung transplant for a cystic fibrosis patient. In order for a successful organ transplant, blood type, human leukocyte antigen (HLA) matching and organ size have to be compatible between the donor and recipient. However, since each individual has very high polymorphism between HLA, the chances of 2 non-sibling individuals having the same HLA phenotypes are very slim. Clinicians will match donor and recipient HLA phenotype as close as possible but rejection is inevitable if HLA phenotypes are different between the donor and recipient. The types of rejection are hyperacute rejection, acute rejection and chronic rejection.

Hyperacute rejection occurs when pre-existing anti-donor antibodies are present within the recipient’s blood which targets the donor organ, causing inflammation to the graft. This can occur within minutes to hours after transplantation. Current practice includes screening for anti-donor antibodies to reduce hyperacute rejection from occurring.

Acute rejection occurs from weeks to months after transplantation and this is due to a mismatch in HLA where antigens from the graft are presented to T cells, thus activating the T cells to target the graft. Depending on the cytokine released, T helper (TH) cells will differentiate into different subsets such as TH1, TH2 and TH17 which will each play a different role in acute rejection. TH1 cells will secrete IFN-γ to activate natural killer cells that will lyse the graft cells while TH2 cells secrete IL-4 to attract eosinophil. Eosinophil targets the graft by releasing inflammatory mediators thus, causing inflammation to the graft. TH17 cells will induce inflammation by producing IL-17. In addition, T cells can strengthen the activation of B cells for B cells to differentiate into plasma cells. Plasma cells will then produce antibodies specific to the graft and induce graft cell death via antibody-mediated cell cytotoxicity (ADCC).

Chronic rejection develops over a period of a few months to years after transplantation. This occurs due to accelerated arteriosclerosis or narrowing of graft vessels and graft tissue fibrosis which often lead to cell death and graft failure.

Fortunately, transplant patients are prescribed immunosuppressive drugs to dampen down the immune response to decrease the chances of acute rejection from occurring. Examples of pharmaceutical agents used as immunosuppressive drugs are tacrolimus, rapamycin and azathioprine. These drugs target and prevent T cell activation which was shown to be the main factor of acute rejection discussed above.

Tacrolimus is a calcineurin inhibitor which inhibits the transcription of cytokine genes such as IL-2 and TNF-α required for early activation of T cells. The decrease in IL-2 prevents T cells to progress from G0 to G1 phase thus, T cells cannot be activated. Rapamycin is a mTOR inhibitor which inhibits the downstream mTOR signalling pathway. This inhibits the proliferation of effector T cells, leading to cell cycle arrest and apoptosis. Azathioprine is an anti-metabolite which interferes with DNA synthesis in the bone marrow and lymph nodes by acting as a purine analogue, incorporating into DNA during DNA replication. This results in DNA damage and ultimately, cell apoptosis.

However, administering these drugs comes with its own side effects such as fibrosis and wound complication from rapamycin and anaemia/ neutropenia from azathioprine. Therefore, the ultimate aim of organ transplant is to achieve tolerance to the graft antigens without the need of immunosuppressive drugs. Research has shown that this is possible by conducting hematopoietic stem cell transplant (HSCT) along with the transplant organ of interest. However, this adoption to clinical practice is yet to be done but might be possible in the future.

Reference:

1. Black CK, Termanini KM, Aguirre O, Hawksworth JS, Sosin M. Solid organ transplantation in the 21st century. Ann Transl Med. 2018 Oct;6(20):409. doi: 10.21037/atm.2018.09.68. PMID: 30498736; PMCID: PMC6230860.

2. Kloc M, Ghobrial RM. Chronic allograft rejection: A significant hurdle to transplant success. Burns Trauma. 2014 Jan 26;2(1):3-10. doi: 10.4103/2321-3868.121646. PMID: 27574640; PMCID: PMC4994504.

3. Sehgal SN. Rapamune® (RAPA, rapamycin, sirolimus): mechanism of action immunosuppressive effect results from blockade of signal transduction and inhibition of cell cycle progression. Clinical Biochemistry. 1998;31(5):335-40.

4. Wood, Kathryn J.; Goto, Ryoichi. Mechanisms of Rejection: Current Perspectives. Transplantation: January 15, 2012 - Volume 93 - Issue 1 - p 1-10 doi: 10.1097/TP.0b013e31823cab44

This article was prepared by Jennifer Chang