Prolonged skin allograft survival after photodynamic therapy associated with modification of donor skin antigenicity.

Abstract

The ability to prolong graft survival, in some cases by depleting donor antigen-presenting cells (APCs), and the subsequent demonstration that lymphocytes stimulated by non-APCs become anergic, suggested that graft survival and tolerance induction might be achieved by manipulating donor APCs to render them incompetent. This possibility was tested in histoincompatible murine skin allograft with photodynamic therapy (PDT). Skin sections (C57BL/6) were exposed in vitro to low doses of benzoporphyrin derivative monoacid ring A (BPD) (verteporfin) and light (A=690+/-10 nm; low-dose PDT) before implantation on recipients (BALB/c). Furthermore, the effect of the treatment on the surface molecules of donor-derived Langerhans cells (LC) was evaluated by fluorescence-activated cell sorter analysis; the effect of treatment on the LC alloreactivity in the mixed epidermal cell lymphocyte reaction was also evaluated. Pretreating skin to be grafted with low-dose PDT can significantly prolong the survival of allografts from 9.3+/-2.2 (n=42) days (control group) to 16.9+/-1.7 days (n=20; treated group). Moreover, low-dose PDT significantly down-regulated the major histocompatibility complex and costimulatory (B7) molecules (60-90% reduction) on LC, but not LC-specific endocytic receptor (DEC-205), CD45, intercellulr adhesion molecule 1, LC viabilities, and ectophosphatase activity on LC. Additionally, this treatment significantly suppressed the ability of LC to stimulate alloreactive T cells to proliferate. Since engaging T cell receptors in the absence of costimulation results in suboptimal activation of T cells and ultimately anergy, it appears that the immunomodulatory effects of low-dose PDT associated with extended engraftment may depend upon decreased LC expression of major histocompatibility complex and costimulatory molecules.