Dendritic Cells: A New Immunotherapy?

Dendritic cells (DC) are sentinels of the immune system. They originate from a bone marrow progenitor, travel through the blood, and are seeded into non-lymphoid tissues. DC capture and process exogenous antigens for presentation as peptide-MHC complexes at the cell surface and then migrate via the blood and afferent lymph to secondary lymph nodes. In the lymph nodes, they interact with T-lymphocytes to facilitate activation of helper and killer T cells.^1,2

DC have been named according to their appearance and distribution in the body (see Table 1). During the past decade, DC have been further characterized by lineage, by maturation stage, by functional and phenotypic characteristics of these stages, and by mechanisms involved in migration and function.^2,3 DC are being considered as adjuvants in immunization protocols for anti-viral or anti-tumor immunity.⁴

Immature DC are defined by cell surface markers that represent functional capacity. They express the chemokine receptors CCR-1, CCR-2, CCR-5, CCR-6 (only CD34⁺ HPC-derived DC), and CXCR-1, commonly thought to allow DC to migrate in response to inflammatory chemokines expressed by inflamed tissues.^5-9 Immature DC are phagocytic and have a high level of macropinocytosis, allowing them to efficiently process and present antigen on class I molecules.^{2, 10-12} Expression of the Fc gamma (CD64) and the mannose receptors allow efficient capture of IgG immune complexes¹³ and antigens that expose mannose or fucose residues.¹⁰ The expression of E-cadherin allows DC to interact with tissue cells and remain in the tissues until activated.

Following antigen processing, DC are remodeled. Fc and mannose receptors are downregulated, and there is a disappearance of acidic intracellular compartments, resulting in a loss of endocytic activity. During this maturation process, the level of MHC class II molecules increases, adhesion molecules and costimulatory molecules are upregulated, and there is a change in chemokine receptor expression.^1-3,5,10,14 Maturing DC home to T cell areas of secondary lymph nodes, where they present antigen to naive T cells. In vitro culture of DC with CD40L, LPS and TNF-alpha generates mature DC. These cells are very good stimulators of allogeneic T cell proliferation.^15-17 The DC-T cell interaction is thought to be a two-way interaction. Evidence suggests that T cells interact with DC through CD40 ligation to enhance DC viability and their T cell stimulatory ability. Addition of CD40L induces DC to produce IL-12, which is known to support Th1 responses.² LPS stimulation generates a weaker in vivo immune response than the CD40L-stimulated DC.¹⁸

The first steps in using DC for clinical applications are the generation of immunostimulatory DC and a decision on the optimal maturation stage for immunization. Typically, maturation stages are assessed using morphology, phenotype (CD83, MHC class II molecules and costimulatory molecules) and in vitro function (antigen processing ability using tetanus toxoid and MLR stimulatory activity). The standardization of maturation assessment criteria and maturation protocols would allow researchers to evaluate the utility of immature vs. mature DC in immunotherapy.

The use of DC for immunization has focused on the generation of cytotoxic T lymphocyte (CTL) responses to tumor or viral antigens.^4,19 Successful, protective CTL responses have been developed in mice immunized with DC pulsed with antigenic peptides and intact soluble proteins.^20,21 Transfection of DC with relevant genes is thought to bypass MHC restriction. Adenoviral and retroviral vectors are also shown to be effective for immunizing tumor-bearing mice.^22-23 Development of monoclonal antibodies recognizing MHC-peptide complexes may help optimize and evaluate antigen-loading procedures for DC. Autologous lymphocytes cocultured with acute myelogenous leukemia-derived DC lyse autologous leukemia targets with little cytotoxicity noted against normal cells from patients in remission.²⁴ DC immunotherapy in vivo and in vitro has shown promising results for cancer treatment and prevention.

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