Ethical issues are an important factor in living donation

The shortage of organs from cadaveric donors has increased the use of living donors. Clearly this is only possible in situations where donation of an organ poses little risk to the living donor. Kidney transplantation is routinely performed from living donors, as it is quite possible to live with just one healthy kidney. It is also possible to donate a lobe of a liver, as it can grow back again. Donation of a lung lobe is also possible, though this is a much riskier procedure. Hematopoietic stem cell transplants also involve living donors, though the issues with this form of transplant are somewhat different than for solid organ transplants as the stem cells are rapidly replaced.

Before any donation from a living donor is carried out, it is important to ensure that the potential donor is healthy, that the donation is compatible (of the appropriate blood group), and that the donor is aware of the risks and has not been coerced into giving an organ. It would be unethical for a donor to be put under extreme pressure to donate an organ, and the transplant teams must take great care to ensure that this is not happening. In the majority of cases donation is carried out between close relatives (including spouses) or sometimes friends. However, there are a few ‘altruistic donors’ that give their organs to be used by whoever needs them. In most countries it is not allowed to sell organs for transplantation, and the majority of those involved in transplantation would see that as unethical. However, there is a real problem with ‘transplant tourism’ where people from rich, developed, countries travel to buy organs from poor, marginalized, donors.

Organ exchange programs have been set up to maximize the number of transplants performed. In the simplest cases these are paired donations. Jane Smith may need a kidney and have a relative, Steve Smith, who is willing to donate it. However, if Steve Smith’s kidney is incompatible with Jane then he cannot donate it to her. However, if there is another couple in a similar predicament, so that Jim Jones needs a kidney and Stella Jones is willing to donate one but they are incompatible, then it might be possible for Stella Jones to donate her kidney to Jane Smith and for Steve Smith to donate to Jim Jones. More complex arrangements are also possible, with three or more pairs donating in such a way as to maximize the number of transplants. Indeed it is possible to use an altruistic donor to initiate a chain of donation, such that they donate to recipient A, recipient A’s potential donor gives to recipient B, their donor gives to C and so on, until the final recipient is an individual who does not have a suitable donor.

In addition to transplantation of organs, there is a large program of transplanting hematopoietic stem cells (cells capable of regenerating blood cells), for example in patients with leukemia or with primary immune deficiencies. These stem cells were previously normally harvested from the bone marrow of (living) donors, though increasingly peripheral stem cells obtained from the blood are used – stem cell transplantation has its own particular problems.

Clinical trials of stem cell therapy, using mesenchymal stem cells or embryonic stem cells are now underway. The aim of these is that the stem cells can differentiate and repair damaged organs. In some cases the stem cells are taken from the patient, in which case there is no immunological issues. However, if they are taken from another individual then rejection is possible.

Host versus graft responses cause transplant rejection

Immune recognition of the antigenic differences between the donor organ and the recipient will, unless treated, lead to an immune response in which the host immune system responds to, and attacks, the donor tissue.

The nature of the host versus graft response is discussed in more detail below.

Similar to any other adaptive immune response, the immune response against a graft shows memory of previous encounters with an antigen. Therefore, once an animal has rejected an organ graft for the first time, if a second graft is performed from the same species or donor then it is rejected more rapidly (second set rejection).

There is a high frequency of T cells recognizing the graft

One of the main features of the immune response against a transplanted organ is that it is much more vigorous and strong than the response against a pathogen, such as a virus. This is largely reflected by the frequency of T cells that recognize the graft as foreign and react against it.

Thus, in a naive or unimmunized individual fewer than 1/100 000 T cells respond upon exposure to a virus or a protein immunization; however, 1/100–1/1000 T cells respond to allogeneic antigen-presenting cells (APCs). This is reflected in the strong T cell response (proliferation) seen when naive T cells are stimulated with allogeneic dendritic cells (Fig. 21.4)

Fig. 21.4 Measuring the strength of the alloresponse

The strength of the alloresponse can be measured in a mixed lymphocyte reaction. In this assay T cells from an individual were mixed with varying numbers of dendritic cells (DCs) from either the same (autologous DC) or a different (allogeneic DC) donor. The dendritic cells were irradiated to prevent their proliferation. As a control cultures were included that contained just the dendritic cells or just the T cells. Five days later, T cell proliferation was measured by incorporation of ³ H-thymidine, which is incorporated into the DNA of dividing cells. There is strong proliferation of T cells exposed to allogeneic dendritic cells, even though these T cells have not been exposed to the allogeneic cells, i.e. it represents a primary immune response.

Histocompatibility antigens are the targets for rejection

Early experiments showed that the bulk of the allospecific response is against molecules of the MHC. We now know that these molecules are the MHC class I or class II molecules (see Chapter 5), which are responsible for presenting antigen (in the form of peptides) to either:

As discussed in Chapter 8, MHC molecules are highly polymorphic, and it is these polymorphic differences that are seen by alloreactive T cells.

Why is there such a high frequency of allospecific T cells?

Several models seek to explain why there is such a high frequency of allospecific cells in the T cell repertoire.

The first model (high determinant density model) (Fig. 21.w1) suggests that allospecific T cells recognize the foreign MHC molecules directly, with a low affinity, in a peptide-independent manner. The affinity of the interaction would normally be too low to activate the T cells; however, because the T cells see the MHC molecules directly, and are not recognizing the peptide, this low affinity is compensated for by the high concentration of MHC molecules on allogeneic cells.

Fig. 21.w1 Why is there a high frequency of allospecific cells?

The high precursor frequency of alloreactive T cells can be explained by one of two models. In the first (high determinant density model) the T cell receptor recognizes the MHC molecules on the surface of the APC with a moderate to low affinity. However, this recognition is largely independent of the type of peptide present in the groove of the MHC molecule. The low affinity of the interaction is compensated for by the multiple interactions that form, which provide an avidity advantage. In the multiple determinant model the T cells recognize, with a high affinity, peptide and MHC molecule complexes. The peptides are derived from normal self proteins. As the T cells have not been tolerated in the thymus to those antigens in the context of the donor MHC (though any T cells reactive with the same antigens in the context of self MHC would have been deleted), there is a high frequency of alloreactivity. Which form of allorecognition is most important will depend on the MHC combination of the donor and recipient.

The second model (multiple determinant model) states that what the allospecific T cells are recognizing are peptides derived from normal, non-polymorphic, host proteins that bind to and are presented by the foreign MHC molecules, but are not presented by self MHC. Due to lack of presentation by self MHC, the T cell repertoire is not tolerant to such peptides. The high frequency of the response is due to the large number of such antigens that can be presented by the graft.

Indirect recognition is important in chronic rejection

In a primary alloresponse (see Fig. 21.4), most of the alloreactive CD4 or CD8 T cells directly recognize the donor MHC molecules.

However, there are other forms of alloresponse, including:

Fig. 21.5 Direct and indirect allorecognition

(1) In direct allorecognition the CD4 or CD8 T cell directly recognizes the donor APC, with the T cell receptor (TCR) binding donor MHC molecules bearing donor peptide. (2) Indirect allorecognition is more similar to conventional T cell recognition, in that the recipient CD4 T cells recognize foreign (donor derived) antigen that has been taken up and processed by recipient APCs. The TCR therefore recognizes recipient MHC bearing donor peptide. CD8 cells only see alloantigen by the direct pathway.

The indirect response is very similar to conventional T cell recognition of normal antigens, such as those from a pathogen, which are processed by host APCs and presented in the context of host MHC molecules.

Nevertheless, the indirect pathway of recognition is important during chronic rejection, when the number of donor-derived professional APCs is no longer high enough to stimulate a direct immune response. It is also important in the rejection of corneal grafts because the cornea lacks large numbers of APCs.

Minor antigens can be targets of rejection even when donor and recipient MHC are identical

Although the MHC is the major target of the alloimmune response, there are also minor histocompatibility antigens. These can serve as targets of rejection even when the MHC is identical between donor and recipient.

The nature of most minor histocompatibility antigens is unknown, though they are assumed to be normal polymorphic molecules, peptides from which bind to host MHC and induce an immune response. In some cases they are expressed in a tissue-specific manner.

Perhaps the best studied minor histocompatibility antigen system is the H-Y system. These are antigens encoded by the Y chromosome, and so are expressed only on male cells. Thus, following immunization, it is possible to demonstrate immune responses and rejection of male organs or skin following transplantation mediated by female animals (2X chromosomes) against male cells (X and Y chromosome). It is not possible to show responses against female antigens by male animals because the male animals have one X chromosome, and so are tolerant to all antigens encoded on it (Fig. 21.6).

Fig. 21.6 H-Y minor histocompatibility antigens

The H-Y antigens are minor histocompatibility antigens expressed on male animals only. Their existence can be demonstrated by skin grafting between animals of the same strain. As would be expected grafts from female mice are always accepted, while those from male mice are accepted on male recipients, but not female recipients.

Graft versus host reactions result when donor lymphocytes attack the graft recipient