Reflections on the Unique Tolerogenicity of Bone Marrow, the Enigma of Chimerism and Clinical Tolerance.
Clinical Transplants 2013, Chapter 18
Since the discovery of acquired immunological tolerance, chimerism has always been associated with tolerance. There is, however, a frequent dichotomy between chimerism and tolerance. Many experimental strategies that produce chimerism do not induce tolerance. In addition, some types of chimerism frequently occur after solid organ transplantation, but rarely result in tolerance. In experimental models of transient lymphocyte depletion with antilymphocyte serum, bone marrow cells exhibit a unique ability to induce allograft tolerance that is superior to that of other lymphoid cells. This tolerance can be augmented with standard immunosuppressive agents used in clinical transplantation. There are currently four ongoing clinical trials of tolerance induction to renal allografts that employ various protocols of non-myeloablative conditioning and donor bone marrow infusion. All four trials have been remarkably successful in achieving short- and moderate-term duration tolerance with minimal morbidity and complications. Persistent tolerance (total drug withdrawal) has been achieved in recipients with durable substantial chimerism. Durable tolerance has also been achieved in recipients who have lost chimerism before or after drug withdrawal has been initiated, as well as in recipients in whom only transient (less than three weeks) or no chimerism at all has been achieved. Although chimeric recipients have rejected grafts during drug withdrawal, durable chimerism is thus far the most positive biomarker for likely successful tolerance induction. At present, there is no proof that chimerism causes tolerance per se; the data are also consistent with another etiological mechanism that causes tolerance and thereby permits chimerism to persist. The current experimental protocols for tolerance induction are safe. More transplant programs should consider doing clinical tolerance research.