Effect of Aging on Host Dendritic Cell (DC) Numbers and Function, and Response to Regulatory DC Treatment in a Murine Allogeneic Transplant Model.

Graft versus host disease (GVH) incidence and severity increases with older patient age. Host dendritic cells (DC) are responsible for initiating GVH, presumably as a result of activation at the time of transplant conditioning (as they are short lived after transplantation). Age-related alterations in host DC function have not been studied in a transplant setting. In this study, young (8–14 wk) and older (12–16 mo) mice were treated with the conditioning regimen of lethal irradiation (1100 cGy) and assessed at 6 h later for changes in DC costimulatory molecule expression and cytokine secretion. Older mice had slightly higher numbers of splenic classical DC (cDC; CD11c^hi Cl II⁺ B220⁻) and plasmacytoid DC (pDC; CD11c^lo Cl II^lo B220⁺) both before and after irradiation. No differences were observed in CD40, CD80, or CD86 expression between young and older mice, either before or after irradiation. IL-12, IFNγ, and TNFα producing cDC were more numerous in young untreated mice than in older mice. However, these cells decreased in young mice and increased in older mice after irradiation, resulting in generally higher numbers of cells producing these cytokines in older mice. IL-12, IFNγ, and TNFα producing pDC were more frequent in older mice than in young mice prior to irradiation, and both older and young mice showed increased frequency of cells producing these cytokines after irradiation. Overall, the highest numbers of cDC and pDC producing IL-12, IFNγ, and TNFα were present in older mice after irradiation. In both cDC and pDC populations, older mice had a higher frequency of IL-10⁺ cells prior to irradiation. After irradiation, young mice had a higher frequency of IL-10⁺ cells. These findings indicate that the balance of cytokine production in older mice after conditioning with irradiation is shifted to immunostimulatory cytokines rather than immunosuppressive cytokines. Murine GVH can be prevented by treatment with regulatory DC (rDC) in young animals (Sato et al., Immunity 2003). To determine whether this treatment is feasible in older animals, older BALB/c mice were transplanted with young C57Bl/6 BM. A subset of each group received age-matched host derived rDC. As expected, among mice that did not receive rDC, old recipients got more rapid and severe GVH than young recipients. This correlated with an increased frequency of residual host DC at the time of GVH in the older group. rDC were used to successfully treat GVH in older (as well as young) transplant recipients. These results provide the foundation for a cell based therapeutic approach to the treatment of GVH in older individuals.