Overcoming immunological barriers in regenerative medicine

Abstract

Regenerative therapies that use allogeneic cells are likely to encounter immunological barriers similar to those that occur with transplantation of solid organs and allogeneic hematopoietic stem cells (HSCs). Decades of experience in clinical transplantation hold valuable lessons for regenerative medicine, offering approaches for developing tolerance-induction treatments relevant to cell therapies. Outside the field of solid-organ and allogeneic HSC transplantation, new strategies are emerging for controlling the immune response, such as methods based on biomaterials or mimicry of antigen-specific peripheral tolerance. Novel biomaterials can alter the behavior of cells in tissue-engineered constructs and can blunt host immune responses to cells and biomaterial scaffolds. Approaches to suppress autoreactive immune cells may also be useful in regenerative medicine. The most innovative solutions will be developed through closer collaboration among stem cell biologists, transplantation immunologists and materials scientists.

Figure 1

The likelihood of encountering immunological barriers depends on the type of cells and tissues used in regenerative therapies. Allogeneic cells of any type are at highest risk for rejection and require tolerance-inducing interventions. Observations from solid-organ transplantation indicate that even in an allogeneic setting the tissue source may also matter, as it is easier to induce tolerance to some allogeneic tissues (e.g., liver) than to others (e.g., skin). Autologous cells can be immunogenic if they have been genetically engineered to express an exogenous protein. Allogeneic cells derived from embryonic stem cells or autologous cells derived from induced pluripotent stem cells may acquire immunogenic features during prolonged culture. Decellularized allografts used as tissue-engineering scaffolds are not expected to encounter substantial immunological barriers because the immunogenicity of extracellular matrix proteins is generally low.

Figure 2

Molecular basis of T cell allorecognition and activation. (a) Allorecognition occurs in one of three ways when T cells interact with allogeneic target cells or peptides. In direct allorecognition, T cells are activated directly by allogeneic cells (antigen-presenting cells (APCs) or any cell expressing allogeneic MHC). T cell receptor activation is triggered by recognition of the complex comprising determinants of the allogeneic MHC class I or MHC class II molecule loaded with peptide (the peptide origin is irrelevant). In semidirect allorecognition, allogeneic MHC class I or MHC class II molecules are acquired and MHC-peptide complexes displayed by autologous APCs. The peptide origin is again irrelevant. For indirect allorecognition to occur, allogeneic transplantation-relevant proteins must first be processed by autologous APCs. Subsequently, peptides derived from these allogeneic antigens are cross-presented by autologous MHCII on autologous APCs. T cell receptor activation is triggered by recognition of the complex comprising determinants of the autologous MHCII molecule loaded with an allogeneic peptide. (b) T cell activation by antigen-presenting cells requires two types of signals. Signal 1 is received by the TCR when it interacts with a cognate peptide-MHC complex. Signal 2 is received by costimulatory molecules (e.g., CD28) when they interact with cognate ligands (e.g., CD80 or CD86). Molecules that inhibit T cell activation and/or induce T cell anergy include cytotoxic T cell lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1). Programmed death ligand 1 (PD-L1) is the main ligand for the PD-1 receptor.

Figure 3

Antigen-specific tolerance induction by apoptotic, polymeric or protein carriers. (a) Autologous splenocytes are treated with ethylene carbodiimide in the presence of exogenous antigen, which results in the production of apoptotic cellular debris that displays the exogenous antigen but not activation signals that induce costimulation by antigen-presenting cells. Intravenous infusion of these apoptotic antigen ‘carriers’ results in T cell tolerance to the exogenous antigens. (b) Donor splenocytes can be treated as in a in the absence of exogenous antigen. In this scenario, T cells are tolerized to endogenous donor MHC molecules and other endogenous alloantigens. (c) Polymeric microparticles can be treated as in a in the presence of exogenous antigens to conjugate the antigen to the microparticle; alternatively, exogenous antigens can be encapsulated within the microparticles. After intravenous infusion, the microparticles are taken up by macrophages that express the scavenger receptor MACRO, and this induces tolerance to the exogenous antigens. (d) Exogenous antigens can be fused to antibody fragments (e.g., single-chain variable fragment, scFv) or other peptides that are specific for proteins expressed on the surface of red blood cells (RBCs). After intravenous infusion, the fusion proteins bind RBCs. Subsequent normal clearance of aged RBCs generates apoptotic RBC debris carrying the exogenous antigen but lacking activation signals. As in a and b, these apoptotic antigen ‘carriers’ induce T cell tolerance.