Xenobiotics, chimerism and the induction of tolerance following organ transplantation

Abstract

The successful results seen after organ transplantation are largely attributable to the potency and specificity of modern immunosuppressive agents. Although drug-free unresponsiveness to graft alloantigens has not been routinely achieved in clinical practice, recent appreciation of the importance of cell chimerism, which develops after the migration from donor to host of leukocytes contained in solid organ grafts, has introduced a concept which may explain the mechanism of graft tolerance. Recent evidence has indicated that immunosuppressive drugs may have a common potential to induce graft tolerance, even though they act through diverse mechanisms, and that this potential may be mediated by a permissive effect on the migration and survival of donor-derived leukocytes. This review briefly examines the mechanisms by which immunosuppressive drugs function and analyses the different methods which these agents might use to induce chimerism associated with graft tolerance. Furthermore, we describe ongoing clinical studies in which the chimerism produced after solid organ transplantation is augmented with donor bone marrow in an attempt to facilitate the induction of tolerance.

Fig. 1

A diagrammatic representation of the immune response during rejection which demonstrates the principal sites of action of immunosuppressive drugs and monoclonal antibodies used to control anti-allograft responses. These agents also have the potential to induce tolerance. APC = antigen presenting cell; Thl/Th2 = T-helper 1 or T-helper 2 cell; T(c/s) = T-(cytotoxic/suppressor) cell; B = B-cell; IL-2R = IL-2 receptor. DSG = deoxyspergualin; MM = mycophenolate mofetil; CsA = cyclosporine A; Cy = cyclophosphamide; BQR = brequinar sodium.

Fig. 2

Progressive development of an understanding of liver transplantation: (a) historical view; (b) realisation (in 1969) that the liver graft became a genetic composite (chimera); (c) proof in 1992 of systemic chimerism. Stars represent the exchange of cells between graft and host.

Fig. 3

Donor mononuclear cells appear in the blood of a human intestinal transplant recipient (a) and interstitial donor leukocytes are progressively replaced within the graft during the same time period (b).

Fig. 4

Detection of chimerism by molecular HLA class II typing in various tissues after liver transplantation in a patient with type 1 Gaucher’s disease. Southern blot analysis of DR1-specific amplification of the DNA extracted from small bowel, skin, bone marrow, blood and liver. The denatured DNA present on the nylon membrane was hybridised to a radioactively labelled DR1 (donor) specific oligonucleotide probe (7001). In the case of the liver, only 1/100 of the amplification product was used.