Clinical Use of Tolerogenic Dendritic Cells-Harmonization Approach in European Collaborative Effort

Abstract

The number of patients with autoimmune diseases and severe allergies and recipients of transplants increases worldwide. Currently, these patients require lifelong administration of immunomodulatory drugs. Often, these drugs are expensive and show immediate or late-occurring severe side effects. Treatment would be greatly improved by targeting the cause of autoimmunity, that is, loss of tolerance to self-antigens. Accumulating knowledge on immune mechanisms has led to the development of tolerogenic dendritic cells (tolDC), with the specific objective to restrain unwanted immune reactions in the long term. The first clinical trials with tolDC have recently been conducted and more tolDC trials are underway. Although the safety trials have been encouraging, many questions relating to tolDC, for example, cell-manufacturing protocols, administration route, amount and frequency, or mechanism of action, remain to be answered. Aiming to join efforts in translating tolDC and other tolerogenic cellular products (e.g., Tregs and macrophages) to the clinic, a European COST (European Cooperation in Science and Technology) network has been initiated-A FACTT (action to focus and accelerate cell-based tolerance-inducing therapies). A FACTT aims to minimize overlap and maximize comparison of tolDC approaches through establishment of minimum information models and consensus monitoring parameters, ensuring that progress will be in an efficient, safe, and cost-effective way.

Figure 1

Adoptive transfer of immunoregulatory function. Transplantation of cells with immunoregulatory function to control unwanted immune reactions is not a new proposition. From the earliest discovery that transferring regulatory cells from tolerant to nontolerant animals could establish tolerance in the recipient, it was suggested that the same principle could be applied therapeutically in man. However, while adoptive transfer became a common experimental practice, its translation to the clinic met many obstacles, not least the difficulty of identifying and isolating human regulatory cells.

Figure 2

Mononuclear phagocytes are vital for control of inflammatory responses. Mononuclear phagocytes are highly adaptable effector cells that engage in diverse, often antagonistic processes: DC and macrophages are capable of both stimulating or suppressing T cell-mediated responses depending upon their state of activation. Under normal physiological, noninflammatory conditions, immature DC and macrophages present self and innocuous antigens to T cells in a subimmunogenic context. Recognition of cognate antigen in the absence of costimulation causes effector T cells to die, become anergic, or convert into regulatory T cells. Thereby, antigen presentation by nonactivated mononuclear phagocytes contributes to the steady-state maintenance of self-tolerance. A second “class” of myeloid regulatory cell arises as a consequence of persistent stimulation with proinflammatory mediators. Such activation-induced myeloid suppressor cells presumably serve as counterregulators that limit self-injurious inflammatory responses. Activation-induced myeloid regulatory cells are phenotypically diverse and operate through a variety of mechanisms, including production of T cell-suppressive soluble factors, receptor-mediated killing of effector T cells, and the activation-dependent induction of Tregs.

Figure 3

tolAPC types being developed as immunosuppressive cell-based medicinal products. The spectrum of myeloid regulatory cell products currently being developed as medicinal products is diverse, so it is valuable to categorise them as cells in arrested states of immaturity (tolDC), activation-induced suppressor cells, or myeloid-derived suppressor cells. Examples of different tolDC products are depicted.