Clinical Transplantation Tolerance Twelve Years After Prospective Withdrawal of Immunosuppressive Drugs: Studies of Chimerism and Anti-Donor Reactivity1

Abstract

Operational tolerance to HLA-A, B, and DR mismatched organ allografts can be induced prospectively in humans for at least 12 years after withdrawal of immunosuppressive drugs. The allograft can be maintained in the absence of detectable donor microchimerism and in the presence of anti-donor reactivity in the mixed leukocyte reaction, suggesting that neither chimerism nor clonal deletion or anergy of recipient T cells to alloantigens presented by donor Class II HLA molecules is required for persistence of the tolerant state using this total lymphoid irradiation protocol.

Tolerance--Is It Worth It?

“…One report documented operational tolerance in heart transplant after total lymphoid irradiation for resistant rejection and subsequent withdrawal of all medications, including immunosuppression, because of drug intolerance (Comerci et al 2009). Similar findings have been found in renal transplants with operational tolerance after total lymphoid irradiation (Strober et al 1989(Strober et al , 2000. A number of case reports have documented spontaneous tolerance in a subset of patients undergoing immunosuppression withdrawal for treatment of PTLD (Orlando et al 2010).…”

Emerging uses for pediatric hematopoietic stem cells

“…Multiple methods of tolerance induction have been proposed (48)(49)(50)(51). There are incidental reports of patients who were removed from immunosuppressants without detectable damage to their transplant grafts (52)(53)(54)(55). Some of these patients have eventually lost their grafts or been found to be undergoing rejection.…”

Challenges to achieving clinical transplantation tolerance

“…A further possible mechanism of immunologic tolerance that is unique to the transplant setting is microchimerism, the persistence of a small number of donor-derived bone marrow cells in recipients (13). However, debate continues regarding methods for detection of microchimerism, the importance of the anatomical sites in which it is found (14), as well as its clinical relevance (15). Whether tolerance or rejection is associated with microchimerism may depend on the state of maturity of the host immune system and the degree of antigenicity of the donor organ (16).…”

“…It is impossible to know how this criterion translates with regard to longevity of human transplants. Furthermore, some reports of human transplant tolerance have subsequently been revised following graft loss (15,18). Accurate methods to measure such tolerance are required, so that we can monitor its induction and its breakdown, should that occur.…”

“…Patients who have stopped their maintenance immunosuppression rarely keep their grafts, but a small number do and somehow maintain a functioning transplant (19). Other examples of patients who require no immunosuppression to maintain the transplanted organ include some who had received total body irradiation as induction therapy for their transplants (15,18) and others who first received bone marrow transplants for hematological diseases and who subsequently were transplanted with kidneys from the same donor. The first such cases were published a decade ago by our group (20).…”