Background

Allogeneic bone marrow transplantation is under investigation for a range of nonmalignant indications, including tolerance induction through mixed chimerism. This strategy has so far been tested experimentally only in young recipients. Due to immunosenescence, older patients have an increase in memory T cells (T MEM) as well as other alterations to their immune system, which may influence the potential to induce tolerance. We therefore investigated the impact of immunosenescence on chimerism-based tolerance induction.

Methods

Groups of young (2 months) and old (12 months) C57BL/6 recipients received BALB/c bone marrow under nonmyeloablative (3 Gy) and minimal (1 Gy) total body irradiation and treatment with costimulation blockade, T-cell depletion, or rapamycin. Multilineage chimerism, clonal deletion, and lymphocyte subsets were analyzed by flow cytometry. Tolerance was assessed by skin and heart grafts and enzyme-linked immunospot, intracellular cytokine, and mixed lymphocyte reaction assays.

Results

Unexpectedly, chimerism and tolerance were established in old recipients with comparable—and in some cases increased—efficacy as in young recipients employing costimulation blockade-based or T-cell depletion-based conditioning with 1 or 3 Gy total body irradiation. T MEM reactivity in (naïve) old mice was augmented in response to polyclonal but not to allogeneic stimulation, providing a mechanistic underpinning for the susceptibility to chimerism induction despite increased T MEM frequencies. Tolerance in old recipients was associated with peripheral and central clonal deletion and a higher frequency of regulatory T cells.

Conclusion

Advanced age does not impair bone marrow engraftment, thereby widening the clinical potential of experimental protocols inducing transplantation tolerance through mixed chimerism.