Cell therapy for autoimmune diseases: does it have a future?

Abstract

Almost all current therapeutic concepts in autoimmune diseases are based on the systemic suppression of immune functions and are not curative. The recent introduction of biologicals such as tumour necrosis factor blocking antibodies or receptors has added greater specificity to efficient management of disease by targeted suppression of rheumatic inflammation. It is evident, however, that only the elimination of the cells secreting inflammatory mediators, rather than the blockade of secreted molecules, will offer real specific therapeutic advantages in the future. Merely the elimination of such cells and also cells controlling the secreting effector cells could be curative and induce true long term remissions. We review here the state of the art and future therapeutic concepts that are based on the specific modulation of pathogenic cells that induce and sustain autoimmune inflammation. This sounds visionary, however, a variety of basic tools are at hand now. Thus, direct and specific cell therapy of rheumatic diseases will become a true alternative to conventional therapies.

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Figure 1.

 The chronic autoimmune reaction. Effector immunocytes as cytokine secreting effector/memory T helper (Th) cells and autoantibody secreting plasma cells are major "players" in chronic autoimmune reactions. In addition, activated antigen presenting cells (APCs) also play an important role in both initiating and sustaining autoimmunity. During chronic inflammation non-professional APCs as B cells also might present autoantigens.

Figure 2.

 In vivo targeting of cells of the autoimmune reaction with antibodies. CD4+ T helper (Th) cells can be efficiently targeted by keliximab (anti-CD4). However, both protective memory and effector Th cells are affected. In addition, the targeting of naive (antigen inexperienced) Th cells (not shown) potentially decreases the overall immune competence for new pathogens, particularly since the naive T cell pools are restored slowly in older people. Rituximab (anti-CD20) is a highly efficient B cell depleting drug. However, it is not able to target long lived plasma cells since these have lost CD20 expression. No feasible antibodies for in vivo targeting of plasma cells have yet been introduced. Polyclonal antibody preparations such as ATG or ALG have been used since a long time for in vivo leucocyte depletion in haematological malignancies. Both reagents usually lead to severe and pronounced in vivo depletion of leucocytes including plasma cells and antigen presenting cells (APCs) (not shown).

Figure 3.

 Targeting antigen presenting cells (APCs)—T helper (Th) cell interaction with CTLA4-Ig. During activation of T cells APCs upregulate CD80 and CD86 that can bind to CD28 on T cells and thereby provide strong costimulatory "signal 2". CTLA4-Ig binds with high affinity to both CD80 and CD86 molecules on the APCs and thereby blocks T cell costimulation leading to anergy or even apoptosis. However, chronically stimulated effector T cells might be less dependent on CD28 mediated costimulation. Thus CTLA4-Ig predominantly modulates primary T cell activation.

Figure 4.

 B cell targeting in autoimmune diseases with anti-CD20. In particular, memory B cells are eliminated during rituximab (anti-CD20) treatment. Depletion of naive B cells is compensated by swift restoration with new B cells from the bone marrow even in older people. While long lived plasma cells lacking CD20 expression cannot be targeted, the supply of pathogenic short lived plasma cells that are generated during activation of autoimmune memory B cells is reduced efficiently. Thereby autoantibody titres originating from short lived plasma cells are decreased drastically (see table) while protective antibodies remain unaltered.

Figure 5.

 Haematopoietic stem cell transplantation for autoimmunity. (A) Chronic autoimmune reaction disturbs the homoeostasis of peripheral immunocyte populations. (B) During immunoablation antithymocyte globulin (ATG)/antilymphocyte globulin (ALG) efficiently eliminate resting long lived plasma cells, antigen presenting cells (APCs), or resting memory lymphocytes, and cyclophosphamide (Cy) targets the differentiation of memory B and T cells into effector immunocytes. (C) Purification of autologous stem cells prevents reinfusion with autoreactive immunocytes. Immune reconstitution with new naive B and T cells help to reset and maintain tolerance and normal immunocyte homoeostasis.

Figure 6.

 Control of pathogenic autoimmune reactions with regulatory T cells. (A) Uptake of target autoantigen via mucosal routes can lead to in vivo induction of regulatory T cells either producing transforming growth factor ß (TGFß) (Th 3 cells) or interleukin (IL)-10 (Tr 1 cells). Both Th 3 and Tr 1 cells target activated antigen presenting cells (APCs) presenting the autoantigen or in the end compete with pathogenic inflammatory T cells (not shown). TGFß and IL-10 also modulate T cell functions. However, active chronic immune reactions might be refractory to modulation by oral tolerance. (B) An alternative strategy involves the isolation of specific regulatory T cells or Tregs from the peripheral blood of patients with autoimmunity. After isolation, autoantigen specific regulatory T cells can be further expanded and reinfused in high numbers back into the patient. At the site of inflammation they exert their suppressive anti-inflammatory effects after specific activation from activated APCs. Here regulatory T cells potentially compete with inflammatory T cells for antigen and growth factors but they also most likely suppress local inflammation through secretion of suppressive cytokines (for example IL-10).