Dendritic cells and tolerance induction

Abstract

Dendritic cells (DC) are widely accepted as the most potent antigen‐presenting cells (APC), and considerable interest has been generated in their potential for the immunological therapy of cancer and infectious disease. Recently, however, a broader understanding of the phenotypic diversity and functional heterogeneity of DC has been acquired. Thus, in addition to having a role in central tolerance, DC are now regarded as potential modulators of peripheral immune responses. Harnessing this potential may offer a new approach to the immunosuppressive therapy of allograft rejection or autoimmunity. Here, the concept of ‘tolerogenic’ DC is placed in the context of rapidly accumulating new evidence of the diverse properties of these important APC.

Adenoviral delivery of CTLA4Ig into myeloid dendritic cells promotes their in vitro tolerogenicity and survival in allogeneic recipients

“…[1][2][3] On the other hand, DC also appear to be specialized for the induction of tolerance, both in the thymus and periphery. 2,4 Maximizing the tolerogenic potential of DC by means that may include their genetic manipulation, offers a potential novel approach to the therapy of immune-mediated disorders, including allograft rejection, autoimmune disease and allergy. Indeed, there is already evidence that immature DC, 8,19 or DC exposed to ultraviolet (UV) irradiation 20 or immunosuppressive molecules (such as IL-10, transforming growth factor ␤ (TGF␤), or CTLA4Ig) 19,[21][22][23] have tolerogenic potential.…”

“…1,3 They also appear to be important in the establishment of central tolerance and in addition, may serve to induce and maintain selftolerance in the periphery. 2,4 The potent immunostimulatory capacity of mature myeloid DC correlates with high cell surface levels of major histocompatibility complex (MHC) class II antigens and of accessory and costimulatory molecules, that include CD40, CD54, CD58, CD80 (B7-1) and CD86 (B7-2). The interaction of CD28 on T cells with B7 ligands on APC provides an essential second signal for T cell activation.…”

Feasibility of CTLA4Ig gene delivery and expression in vivo using retrovirally transduced myeloid dendritic cells that induce alloantigen-specific T cell anergy in vitro

“…There is ample evidence that DC are the primary instigators of naive T cell activation, and that they may determine the balance between tolerance and immunity. [1][2][3][4]41,42 The potential of these rare BM-derived APC to act as natural immunologic adjuvants has provided the basis for the evaluation of DC-based vaccines, including genetically engineered DC, for anticancer therapy. 33,34 On the other hand, DC appear to play important roles in central and peripheral tolerance.…”

“…33,34 On the other hand, DC appear to play important roles in central and peripheral tolerance. 2,41,42 Thus, DC are instrumental in the induction of intrathymic self-tolerance. 43,44 It has also been postulated that thymic DC, trafficking to the periphery, may be involved in the development of systemic tolerance following intrathymic Ag injection.…”

Gene- and cell-based therapeutics for type I diabetes mellitus

“…DC tolerogenicity manifested as the suppression of T-cell activation has been documented in tumor, allo-and autoimmunity. 90 Therapeutics 90,[94][95][96][97][98] With the aim of establishing a durable tolerogenic state in the recipient of an allogeneic transplant, myeloid DC have been genetically modified using adenoviral and retroviral vectors encoding CTLA-4Ig, TGF-b and IL-10 in the mouse. [91][92][93] .…”