Immune Responses to Transplants

Last lecture for Immunology!

Transplants can be very useful in extending the lives of seriously ill patients for a few more years. Some common transplants are kidney transplants, as donors can survive with one less kidney, and bone marrow, which can help treat immunocompromised patients (as outlined here).

The issue with transplants is that the immune system may see the transplanted tissue as a foreign entity and attack it. The likelihood of this happening increases with the degree of "foreignness," which is a concept I touched on a while ago when talking about immunogenicity. An autograft, which is the least likely to be rejected, is derived from your own tissue (e.g. from stem cells collected at birth). Isografts come from identical twins, allografts come from unrelated members of the same species, and xenografts come from different species.

Rejection of grafts is mediated through several different pathways, such as T-cells and antibodies, as I'll explain in a bit. Memory cells can also be formed, so while transplant number 1 might take around 10 days to be rejected, transplant number 2 from the same donor will be rejected in only a few days. Because all of this requires a working immune system, nude mice (which lack a thymus) will happily accept grafts without any issue.

MHC molecules are some of the major antigens involved in rejection. Direct allorecognition is when the recipient's T-cells recognise "foreign" MHC molecules on the APCs from the donor. Aside from MHCs, there are also minor histocompatibility antigens (as opposed to the major ones), which are other proteins that differ from person to person. For example, males have H-Y antigen whereas females do not, so in a transplant from a male to a female, the female's immune system cells may react against it.

Thankfully, we don't just have to rely on trial and error to see if a donor and recipient match well or not. MHC testing can be carried out through several different methods. In one method, PCR is used to figure out which MHC molecules a person has (i.e. which haplotype). The other method is called Mixed Lymphocyte Reaction, or MLR, and involves mixing together T-helper cells from the recipient with APCs from the donor. These cells are also mixed with ³H-thymidine, a radioactive molecule that can be inserted into the DNA of proliferating cells. If the T-helper cells recognise the foreign class II MHC in the APCs, they will become activated and proliferate, taking up ³H-thymidine in the process. Uptake can be measured, giving an indication of whether or not the recipient will react against the donor cells or not.

As mentioned earlier, antibodies and T-cells can play a role in rejection. If the person already has antibodies against donor antigens (such as in the case of blood donation), then the rejection reaction happens very quickly, and is classified as "hyper-acute." Antibodies binding to donor tissue result in activation of complement, formation of immune complexes, formation of the MAC complex and so on, ultimately resulting in inflammation and other undesirable effects such as obstruction of blood vessels.

T-cells can also fight off a graft in pretty much the same way they fight off everything else, after first recognising foreign MLC and/or foreign peptides. That is, helper T-cells produce cytokines, cytotoxic T-cells kill stuff, and so on. These responses can be suppressed with several medications. Rapamycin blocks lymphocyte proliferation, whereas corticosteroids jut have general anti-inflammatory effects. Unfortunately, this can leave the patient at greater risk of infection.

Rejection can be classified according to the length of time over which the process occurs. Hyper-acute reactions, which occur within 24 hours, are mediated by preformed antibodies. Acute rejection, which takes from 10 days to a few weeks, relies on general humoral and cell-mediated immunity processes. Chronic rejection, which is often just the acute rejection process drawn out over time by immunosuppressants, can take several months to years. This is sometimes also mediated by minor histocompatibility antigens.

One special case that I want to touch on is that of bone marrow transplants. Bone marrow transplants are usually given to patients with severe immunodeficiency in order to help them "grow a new immune system." Here, since the patients are immunocompromised, the issue of the host rejecting the graft isn't so much an issue. Instead, there's an issue in which the immune cells in the graft might reject the host, causing a "Graft vs. Host (G vs. H)" reaction. In order to prevent this from happening, anti-CD3 is added to remove donor T-cells from the graft before transplantation. The recipient is also gamma-irradiated in order to kill off any immune system cells that they might have so that the donor cells can completely replace theirs. If donor T-cells are not eliminated, symptoms of G vs. H reactions, such as skin rashes, fever, anaemia, weight loss and diarrhoea, may occur. In extreme cases, this can be fatal.

Perhaps not the nicest note to finish on, but that's it for Immunology!