Killer aAPCs as tools for immunosuppression

Schütz and colleagues have generated killer artificial antigen-presenting cells (κaAPCs) by coupling an apoptosis-inducing α-Fas (CD95)–IgM mAb together with HLA-A2-IgG1 molecules covalently on the surface of epoxy beads. Specific T-cell depletion was rapidly achieved in 30 minutes in a Fas/FasL-dependent fashion using these κaAPCs. Deletion of CD8⁺ T cells in an antigen-specific fashion was demonstrated for 2 T-cell specificities and was clearly related to the number of κaAPCs present.

Current approaches to treat or prevent T cell–mediated pathogenesis are mostly based on immunosuppressive drugs that globally suppress the immune system, thereby rendering patients susceptible to infections and the development of secondary tumors. Thus, alternative strategies to prevent and treat autoimmune and alloimmune reactions are evaluated by Schütz and colleagues.

One of these approaches is the transfer or induction of T regulatory cells (Tregs) for preserving and restoring tolerance to self-antigens and alloantigens.^1,2  Evidence from animal models has shown that the transfer of regulatory cells or tolerogenic dendritic cells to induce regulatory cells in vivo can prevent or cure transplant rejection/graft-versus-host disease (GVHD), or re-establish self-tolerance in autoimmune disease. To become a viable clinical approach in the prevention and treatment of autoimmune disorders and GVHD or transplant rejection, better surface markers are urgently required that are specific for human Tregs. In addition, insufficient expansion of these cells and lack of purity of the expanded cells are still problems to be solved; clinical studies of GVHD prevention by transfer of Tregs are ongoing.

Another approach to inhibit or delete autoreactive or alloreactive T cells in the setting of autoimmune disease or GVHD is based on antigen-presenting cells that express the apoptosis-inducing ligand FasL. Genetically modified dendritic cells (DCs) expressing FasL can be used for antigen-specific deletion of cytotoxic T lymphocytes (CTLs). Coupling HLA-A2-IgG1 and α-Fas IgM mAb on epoxy beads has several advantages when compared with genetically modified DCs. κaAPCs do not require time-, cost-, or labor-intensive preparation; these modified beads can be produced in sufficient numbers at high quality. In contrast to antigen-presenting cells, the modified beads present only HLA molecules loaded with one defined peptide, which prevents induction of T-cell apoptosis with other specificities due to the presentation of a range of peptides on DCs that express apoptosis-inducing FasL. Additionally, beads coupled with CD95-IgM and HLA-A2-IgG1, in contrast to modified DCs, do not express costimulatory molecules, which could impair induction of apoptosis by Fas-FasL interaction on CTLs with the defined specificity.

κaPCs have been used to delete antigen-specific T cells in vitro and also in vivo in a mouse model,³  significantly suppressing the occurrence of GVHD. One major limitation of κaAPCs in potential clinical application is their dependency on HLA-A2, at least at the moment; the availability of a defined HLA-A2–restricted, disease-relevant T-cell epitope is another.