Passive enhancement

The use of antibodies to donor histocompatibility antigens to suppress graft rejection was first demonstrated in tumor transplantation studies in the early 1950s. When passive enhancement was tested with skin grafts, its effect was noted to be weak. Graft survival was prolonged by only 2 or 3 days, and the clinical applicability of this approach was not considered of any great interest. However, the development of microsurgical techniques in the 1960s made possible the use of vascularized heart and kidney allografts in studies in inbred rodents. By the late 1960s, French and Batchelor in the UK and FP Stuart and his coworkers in the USA had established that passive enhancement was remarkably successful at suppressing kidney graft rejection in rats. Treatment of graft recipients with one or two injections of anti-donor antiserum at the time of grafting could suppress the rejection response completely, and result in life-long acceptance of major histocompatibility complex (MHC)-incompatible kidney grafts. This caused considerable excitement at the time, and the first attempts to reproduce this phenomenon in the clinic were reported in the early 1970s.

Mechanisms

The mechanisms whereby passive enhancement suppresses rejection is not clear. The most likely possibility is that the antidonor antibodies interact with the interstitial dendritic cells (passenger leukocytes) of the graft and thereby prevent these highly immunogenic cells from stimulating the host's immune system.

Specificity of the enhancing antibodies

Antibodies to both class I and class II MHC antigens of the donor have been shown to be effective for passive enhancement. However, it is possible that anti-class II antibodies might be more effective.

The importance of the Fc region of enhancing antibody

There are many conflicting reports on the efficacy of the different classes and subclasses of antibody for passive enhancement. Overall, it is likely that immunoglobulin M (IgM) is not very effective and that the complement fixing classes (e.g. IgG2a in the mouse) are most effective. What is clear, however, is that F(ab')2 fragments of enhancing sera are totally ineffective, and this is an important point to note.

Potency of passive enhancement

The high hopes for passive enhancement stemmed from studies with organ grafts in inbred rats. Even here, however, the efficacy varies markedly in different donor/recipient strain combinations. Several attempts at passive enhancement in larger experimental animals (dogs, primates) have been disappointing. Passive enhancement is clearly a relatively weak form of immunosuppression, but one that could make a contribution as part of a more complex protocol for immunosuppression.

The problem of hyperacute rejection

In humans and most large experimental animals, the presence at the time of grafting of antibodies to donor histocompatibility antigens results in immediate graft destruction ('hyperacute' rejection). This is caused by the interaction of the antibodies with the vascular endothelial cells of the graft, the fixation of complement and the consequent triggering of intravascular blood coagulation and vascular spasm. For reasons which are not entirely clear, this does not occur in most donor-recipient strain combinations studied in the rat. This has allowed passive enhancement to be studied in great detail in inbred rats.

However, the injection of antidonor antibodies in the clinical situation carries the risk of inducing hyperacute rejection. The early clinical studies attempted to overcome this problem by using F(ab')2 and Fab fragments, because these preparations would not fix complement. However, it later became clear that such fragments are totally without enhancing activity. The use of noncomplement fixing IgG subclasses for passive enhancement is probably the only available option. In fact, noncomplemcnt fixing mouse IgGl monoclonal antibodies to polymorphic determinants of rat MHC antigens have been shown to be effective for passive enhancement, although large doses of antibody were required.

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