4.3.4. Tolerance

Principles of stem cell biology and cancer: future applications and therapeutics. Edited by T. Regad, T. J. Sayers and R. C. Rees. John Wiley & Sons (2015)

Part I. Stem Cells

HSC transplantation can also be used to induce tolerance for a subsequently transplanted solid organ. ‘Tolerance’ here would be defined as the ability to accept a transplanted organ as self, while retaining (near) normal immunological competence. This principle has been recognized for over half a century, following pioneering work by Peter Medawar and others. Implementation has lagged due to the morbidity and mortality associated with allogeneic bone marrow transplantation, however.

Organ transplantation is currently dependent on the continued use of immunosuppressants to prevent rejection. While successful in the short term, long-term survival is limited. Ten-year survival ranges from approximately 60% of transplanted organs (heart, liver) to barely 25% (lungs, small bowels) (HHS/HRSA/HSB/DOT, 2009). In addition, continued immunosuppression is associated with complications, including renal and neurotoxicity and opportunistic infections (Mueller et al., 1994; Cattaneo et al., 2004; Kalil et al., 2007; Vajdic and Van Leeuwen, 2009). Multiple methods of inducing tolerance have been proposed and tested, mostly with only incidental success (Table 4.3) (for reviews, see Gandy et al., 2007; Sykes, 2009; Bluestone, 2011; Strober et al., 2011; Domen et al., 2012; and Leventhal et al., 2013b). These include costimulatory blockade, microchimerism and T cell depletion. More successful have been approaches involving HSCs, several of which continue to be developed and will be discussed in more detail in this section.

Experimentally, tolerance can be induced by different types of HSCcontaining preparations, including both mixed populations and rigorously purified HSCs. Other haematopoietic cells, including regulatory T cells, macrophages and dendritic cells, have also been used to protect grafts experimentally. Clinically, the complications associated with allogeneic HSCT continue to be a major hurdle. Several strategies for overcoming this are under active development. The combination of total lymphoid irradiation (TLI) and HSCT has shown promise in clinical trials (Scandling et al., 2012). Sublethal preconditioning has also been pursued systematically (Sachs et al., 2011), while the use of so-called ‘facilitator cells’ – cells that can facilitate allogeneic engraftments (Gandy et al., 1999) – has recently shown clinical promise in tolerance induction protocols (Leventhal et al., 2013a). The use of progenitor cells may be promising in combining some of the reduced toxicity of more mature cell therapy with the ability to address several different tolerance induction mechanisms of HSC therapy (Domen et al., 2011). However this approach, while promising, is still strictly preclinical.

Table 4.3. Comparison of standard immunosuppressant therapy with therapies aimed at inducing tolerance.

Therapy Use Outcome
Immunosuppressants Standard therapy Effective in short term, less so in the long term; significant side effects
Costimulatory blockade, T-cell depletion Trials Limited effectiveness alone, may be good in combination therapy
HSC transplant (BMT, MPB, UCB) Trials Very effective; works at multiple levels and through many mechanisms; severe comorbidity
Progenitor cell therapy, e.g. myeloid progenitors Experimental Effective; may work through different mechanisms
Other cellular therapies (Treg, macrophages, dendritic cells) Trials Promising but addresses fewer issues (single cell type)

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