Accommodation_Tolerance - Professor Richard Kirk 2023

Professor Richard Kirk
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Accommodation and Tolerance
Accommodation refers to the observation that graft function may be unaffected by the presence of donor specific antibodies. It is a different concept to tolerance (see below) where the donor specific antibodies disappear. It is well recognised in ABO mismatched transplants but may also be seen post transplant where high levels of HLA DSA titres (MFI >10,000) may be found many years after transplant with normal cardiac function.

Accommodation may occur due to changes in the transplanted organ (graft), changes in the host immune system or a combination. Changes in the graft may include modification of the signal (antigen expression), or resistance to injury (for example heparin sulphate on the cell surface is known to inhibit complement activation and increases in the concentration may reduce cell injury). Host changes may include class switching of immunoglobulin e.g. from IgG1 to IgG2, the latter is less effective at binding complement). Likewise T cells may shift from Th1 cells to Th2 cells or their may be changes in presence of CD4+ T helper cells.
Detailed description of the possible mechanisms of accommodation are not possible here but explained well in this excellent article by Koch et al. J Immunol 2004;172:5143
The holy grail of transplant medicine is tolerance. Most post transplant complications are related to acute, sub acute and chronic rejection and the effect of immunosuppression and the medications. Unfortunately tolerance has yet to be achieved, at least in cardiopulmonary transplants. Undoubtably some persons appear to have a natural tolerance to their graft. They appear to remain rejection free with low levels of immunosuppression (or even none - as some choose to stop it all together). This situation may be due to a happy coincidence of a close HLA match to the donor or natural reduced HLA expression on tissues and immune cells. However tolerance is seldom an all or nothing phenomenon and even those apparently tolerant may experience rejection if the quiescent immune system is upregulated e.g. with an infection.
It is clear that the immune system is complicated and our understanding incomplete, despite considerable research exploring the many components that may play a part in down regulation of the immune system and possible tolerance.

It has been recognised for a long time that multiple organ transplant e.g. lung and liver, require immunosuppression at a level necessary for the organ requiring the least immunosuppression. The hierarchy is usually bowel, lung, heart, kidney, liver with the bowel requiring most immunosuppression and liver the least. In renal transplantation bone marrow and renal transplants have been performed to achieve tolerance but this requires an identical sibling to provide the stem cells and kidney - an unusual circumstance.

T cell development requires a thymus and B cells require the cooperation of T cells to activate. Some genetic conditions have thymic aplasia (e.g. "complete" Di George syndrome). In these patients there is  compete lack of T & B cell immunity and death from infection has been almost universal by 2 years of age. The team at Duke University, USA led by Louise Markert have pioneered the use of thymic transplants in these patients with considerable success. Recently such a patient also had severe congenital heart disease and ultimately underwent a combine heart-thymus transplant. Evidence to date suggests that the child may well be tolerant of the donor heart however much more work needs to be done to explore the possibility of solid organ and thymic transplantation - especially when the recipient has a competent thymus.
  • Thymic transplantation. Markert, Devlin and McCarthy. Clin Immunol. 2010;135: 236–246. doi:10.1016/j.clim.2010.02.007
  • Introducing thymus for promoting transplantation tolerance. Fitch et al.  J Allergy Clin Immunol 2022.
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