The impressive results obtained with high-dose lymphoablative/myeloablative conditioning regimens are in accordance with the current concept that autoimmune diseases are maintained by activated T cells. These have to be inactivated or eliminated as much as possible in order to achieve complete and lasting remission. The animal experiments are equivocal in demonstrating that treatment with lower doses of the various cytotoxic agents results in incomplete responses and more relapses. It is therefore unlikely that so-called nonmyeloablative conditioning will be useful, unless the degree of T-cell ablation achieved can match that of current myeloablative regimens. It is obvious that the more vigorous ablation carries a higher risk of treatment-related morbidity and mortality. The optimal regimen needs to be defined in the clinic for each category of autoimmune disease.
The finding that cyclophosphamide as the sole conditioning agent is less effective than high-dose TBI or the combination regimens implies that less lymphoreduction is achieved with cyclophosphamide. Many clinical teams prefer the use of cyclophosphamide alone or combined with antilymphocyte globulin for conditioning. TBI is not favoured, mainly because it increases the risk of cancer. However, cyclophosphamide is an alkylating agent and is therefore carcinogenic, as is prolonged treatment with high-dose immunosuppressive agents (for review [11]).
How can the excellent results with autologous stem cells in animal models and the encouraging preliminary results with this modality in patients be explained? The current hypothesis is that the reconstitution of the immune system from a few haematopoietic stem cells represents a recapitulation of ontogenesis, with the acquisition of self-tolerance. This theory is based mainly on the experience with grafting of purified allogeneic stem cells, which may lead to full reconstitution of the immunological system in the absence of graft-versus-host disease.
The most intensive conditioning gives the best results because it eliminates the highest proportion of autoreactive T lymphocytes. It stands to reason that this effect will be undone if T cells in the autograft outnumber those surviving in the patient. A rough estimate of the surviving fractions are available only for TBI, and is between 0.1 and 0.01% for the most effective dose (ie 9-10Gy) [11]. Because of these uncertainties it seemed prudent to begin clinical studies with maximally depleted autografts. The recommendation to graft no more that 105 T cells/kg [12] was based on the capabilities of current CD34 cell selection techniques. However, these also remove B cells, natural killer cells and macrophages, which is unnecessary and possibly harmful. Such rigorous depletion may result in a prolonged period of severe immunosuppression with risks of infections and lymphoproliferative malignancies. Data from the most sensitive model (EAE) suggest that 2×106 T cell/kg would still be safe, and this level can be achieved by specific depletion methodology.
Finally, there is the option of using allogeneic stem cells, which in the EAE rat minimizes relapses due to its graft-versus-autologous T-cell effect [13]. Considering the higher risks of transplantation-associated mortality, the clinical exploration of allogeneic BMT should be postponed until it becomes clear from ongoing studies with autologous stem-cell transplants which patients might benefit. For the treatment of connective tissue type autoimmune diseases, allogeneic stem cells cannot be recommended because graft-versus-host reactions are very difficult to distinguish from lesions due to the original autoimmune disease. It has been suggested that the induction of mixed allogeneic chimerism might be an attractive option, by virtue of a graft-versus-host autoimmunity effect in the absence of toxicity and graft-versus-host disease. Apart from the problem that such induction is as yet far from standardized, our results with mixed chimeras in EAE revealed a very high incidence of relapses [14].
For the time being it seems that the available animal models have been rather exhaustively employed for generating the essential preclinical data [15]. They are not suitable to sort out more subtle details for the optimization of treatment. The large variety of autoimmune diseases and the variation of disease manifestations within each disease cannot be imitated in much detail in the laboratory. If the accumulated clinical experience with autologous stem-cell transplants identifies specific fundamental questions, the animal models might again become useful.