Organ rejection occurs when a transplanted organ is rejected by the host's immune system. On a molecular scale this happens when T-cells or T lymphocytes are triggered by foreign Human Leukocyte antigens, and then activated by contact with MHC (Major Histocompatibility Complex) proteins. However before T-cells are activated, they must differentiate (become more specialised.) Once the T-cells have differentiated (in this case into cytotoxic T-cells) and the MHC molecule is displayed on the surface of a cell, along with normal proteins and microbial invaders (which all play a role in the immune system) can necrosis of tissue occur (Frohn, C. et al, 2001). Rejection occurs in two stages, the first being sensitization, which is relatively simple. This is when lymphocytes are alerted and respond to foreign MHC molecules, causing rapid proliferation. However the second stage is much more complicated, this includes two types of mechanism's, cellular and molecular (Thorogood, J. et al, 1990). The cellular mechanism includes two models which focus on the effecter mechanisms of CD4+ (helper) T-cells and CD8+ (cytotoxic) T-cells, which are instrumental in coordinating transplant rejection pathways.
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The first model is called 'the mixed lymphocyte reaction.' This is when CD8+ cells differentiate into CTL's (cytotoxic T-cells) and CD4+ differentiate into cytokinine producing helper T-cells. "The CTL can now recognize specific antigenic peptides expressed on class 1 MHC molecules (which encode non-identical pairs of peptide binding proteins) and the CD4+ helper cells are stimulated by fragments of microbes destroyed by class 2 MHC molecules, also known as antigen-presenting cells" (Iannacone, M., Sitia, G., Guidotti, L. G. 2006). When class 1 and 2 MHC's of both stimulator and responder cells are the same, few CTL's are generated therefore proliferation occurs and there is a mismatch in the HLA loci, this means that the organ is a bad donor match
The second model includes the stimulation of T-cells through recognition of MHC molecules at both class 1 and 2 sites, which as previously discussed leads to CD4+ and CD8+ activation. However in this model, APC's enter through blood or lymph nodes. Donor recipient APC's then infiltrate the graft and 'pick up' donor allo-antigens. These are transported along lymph vessels to the lymph nodes, which in turn activate lymphocytes causing massive lymphocyte proliferation (Gao, J. F. et al, 2010).
Figure shows healthy islets (center) surrounded by non-insulin producing pancreatic cells
Figure shows hyperacute rejection in progress: Islets (center) are being filtrated as part of immune system attack.
Figure show the pathways of antigen presentation
The second mechanism of rejection focuses on a molecular lever and is based on the recognition of foreign transplanted cells by the expression of polymorphic and co-dominant genes. These genes, code for proteins, known as antigens, which are expressed on the surface of cell. MHC is responsible for the most rapid form of rejection. MHC is encoded by the MHC complex which is a region of genes found on chromosome six in humans. MHC is then presented to T-cells in two ways (Thorogood, J. et al, 1989). The first way is through direct presentation (fig1.) Host TCR's (T-cell receptors) recognize foreign MHC-peptide presented by Antigen Presenting Cells. If there are enough similarities of self/non-self MHC's, then T-cells are able to recognize a single MHC molecule, due to their polymorphic nature and amino acid residue, also several classes of T-cells can recognize single MHC molecules, with each foreign cells having up to fifteen copies of a single MHC, (Birkholz, K. et al, 2010) however through in-direct presentation recipient APC's are able to process donor antigens and present them to T-cells using self MHC's, the hosts APC then engulfs the foreign antigens. The peptide fragments are then presented by host MHC's to either CD4+ or CD8+ T-cells (Iannacone, M., Sitia, G., Guidotti, L. G. 2006). There are three types of rejection that can occur from organ transplantation. These are hyper-acute, acute and chronic. Hyper-acute rejection occurs within the first 24 hours after transplant, and is known as a "compliment-mediated response." This is because the transplanted tissue never becomes vascularised, and is characterised by thrombotic occlusions and haemorrhaging of graft vasculature. Hyper-acute rejection is caused by pre-existing host antibodies which bind to antigens on the hosts endothelium. This then activates the compliment system, causing an influx of neutrophils into the region. Neutrophils induce endothelial cells and platelets to shed lipid particles from the membrane of the host, therefore coagulation is promoted and vascularisation is prevented causing Ischemia. "Hyper-acute rejection is the outcome of xenotransplanted organs in non-immunosuppressed patients" (Wu, S. L. et al, 2010). Acute rejection happens after one week and occurs to some degree in all patients (with one exception in identical twins.) "This is caused by mismatched HLA antigens which are polymorphic in nature and therefore a match is extremely rare. The reason it takes a week is due to the differentiation of T-cells and the production of antibodies for rejection" (Cui, J. et al, 2010). T-cells cause graft cells to lyse and produce cytokinines that recruit other inflammatory cells causing necrosis. The earliest victims of graft rejection are the endothelial cells of the kidneys.Figure shows arterial occlusions
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Chronic rejection occurs months to years after implantation and is characterized by arterial occlusions (fig 3) which result from proliferation of smooth muscle cells and production of collagen by fibroblasts. This process (graft artereo sclerosis) results in ischemia and cell death. Fibrous legions occur without evidence of an overt cause. It is hypothesised that chronic rejection results from prolonged multiple acute rejection, based on the resulting fibrosis, similar to fibrosis that accompanies healing.
Figure Fig 4 shows the percentage of graft survival in patients receiving various transplants after 1 year and 5 years
Unfortunately organ rejection in chronic patients is irreversible, however recently ciclosporin has been investigated for the use of slowing down the effects of chronic rejection in lung transplant patients(need to ref) although for the moment the only effective treatment is the re-transplantation of another organ. With organ rejection in acute patients, immunosuppressive drugs, such as mTOR and Corticosteroids can be used to suppress the immune system. Corticosteroids are usually used as a short course, which is sufficient enough to treat successfully, although they can be used on a triple regime along with calcineurin inhibitor and anti-proliferant agents.
These methods of treatment have varying effect from the first year after transplantation to five years after, for example 93.8% of kidney transplants and 80. 7% of pancreas transplants survive after one year, however survival in pancreatic replacements after five years is significantly reduced to 32%. (tom - Ref last paragraph from brown website)