Graft vs. Host

One of the most pressing needs in organ transplantation is the availbility of matched donor material - what this 'matching' specifically means is explained below. Mis-matching of donors and rejection of organs unfortunately happens quite often, and recipients require life long immunosuppressents to dampen the ensuing rejection, or in severe cases a new transplant.

The reality and severity of donor mis-matching was clarified recently when  I saw an image of a patient with graft vs host disease (GVHD). In this setting it is the transplanted donor material which attacks/rejects the recipient, rather than the recipient rejecting the donor organ.

Previously I had been taught about whole organ GVHD, whereby the transplanted organ harbours immune cells capable of attacking the recipient. This is especially serious when the transplant recipient is immunocompromised. However, the more serious aspect of this disease occurs in patients who have received bone marrow containing hematopoetic stem cells (see image left).

The basis of organ rejection and GVHD surrounds the interaction between molecules on tissue cells and receptors which recognise them on immune cells. The former are called HLA (human leukocyte antigen), broadly separated into 2 classes of MHC (major histocompatability complex) designated I and II. These molecules are capable of showing the immune system parts of proteins being synthesised within the cell (known as peptides). This mechanism forms part of an incredibly evolved host defence system, as if the cell is infected with a virus or bacterium, immune cells can detect the protein sequences on HLA as foreign, and discreetly kill the cell - halting the spread of infection.

Receptors which recognise HLA and protein peptide sequences are present on a subset of cells called T lymphocytes (T-cells). T-cells recognise foreign proteins and orchestrate the death of the cell through a variety of direct and in-direct mechanisms (see image below-right for the interaction between HLA (MHC molecule) - peptide and T-cell receptor).

Individuals having undergone radio- or chemo-therapy to irradicate blood-born cancers (e.g. Leukaemia) require bone marrow transplants containing immune cell precursors to 're-fill' their depleted immune cell compartments. T-cells arising from donor bone marrow are capable of recognising foreign HLA expressed on tissues. This occurs by either directly binding to them on cells, or in-directly recognising foreign HLA protein peptides presented on their own HLA molecules. The result is always the same however - death of the cell expressing foreign HLA. Other immune cells also play a role in the initiation of 'allo' (non-self) responses. B lymphocytes (b-cells) produce antibodies which can directly recognise foreign HLA and initiate cell death. Matching donors with recipients for transplantation compares the types of HLA molecules expressed by each individual. A matched transplant would mean that neither host nor recipient recognise each other as foreign, and therefore no transplant rejection or GVHD. There are however a huge number of HLA types, several of which are expressed in any one individual, which means there is a large number of possible HLA combinations which need to be matched.

The best organ or bone marrow donor would be the recipient's identical twin, and the next best chances for having a donor with matching HLA would be a sibling - as HLA proteins are inherited from both mother and father.

Most whole organ recipients require immunosuppressants, however in bone marrow donors this would defeat the point of the transplant. When donor and recipient are not properly matched the result is dramatic, as the donor's bone marrow derived immune cells destroy the recipient.

I haven't included any images like the one I saw, as their are no advisory warnings on the blog. A reliable resource for symptoms and treatment can be found here. The need for better HLA matching, and essentially a greater pool of donors to select from is a priority for proper treatment of individuals needing transplants.