Cell Based Treatment of Autoimmune Diseases in Children

Abstract

Mesenchymal stem cells have recently been recoined as medicinal signaling cells (MSC) for their ability to promote tissue homeostasis through immune modulation, angiogenesis and tropism. During the last 20 years, there has been a plethora of publications using MSC in adults and to lesser extent neonates on a variety of illnesses. In parts of the world, autologous and allogeneic MSCs have been purified and used to treat a range of autoimmune conditions, including graft versus host disease, Crohn's disease, multiple sclerosis, refractory systemic lupus erythematosus and systemic sclerosis. Generally, these reports are not part of stringent clinical trials but are of note for good outcomes with minimal side effects. This review is to summarize the current state of the art in MSC therapy, with a brief discussion of cell preparation and safety, insights into mechanisms of action, and a review of published reports of MSC treatment of autoimmune diseases, toward the potential application of MSC in treatment of children with severe autoimmune diseases using multicenter clinical trials and treatment algorithms.

Keywords: autoimmune; children; mesenchymal; stem cells; transplant; treatment.

FIGURE 1

Pediatric rheumatology is involved in inflammatory conditions in children that range from monogenetic (A), i.e., autoinflammatory syndromes to polygenic (B,C). The latter can be one time occurrence (B; such as Kawasaki Disease or MIS-C) or chronic and long term (C). Autoimmune conditions (C) can be systemic (i.e., affecting 2 or more target organs; such as SLE, JDMS, SSc) or single organ specific (such as Rheumatoid factor + RA, T1DM, autoimmune thyroiditis, uveitis, IBD and Multiple Sclerosis). We postulate that most conditions under B are triggered by infections and the determining factor between the two polygenic inflammatory conditions (B,C) is the presence or absence of an adversary immune memory. Should breakage of tolerance occur, there might be a progression from (B,C) (such as reactive arthritis to chronic arthritis) at varying speed and intensity based on host HLA, genetic risk factors, immune -repertoire and -memory, and the properties of the triggering event.

FIGURE 2

Preclinical studies have shown effects of MSC on cell viability, proliferation and differentiation toward preserving homeostasis. These are highly coordinated activities delivered through evolutionarily conserved mediators as well by cell-to-cell contact toward promoting angiogenesis, tropism and/or immune modulation. These activities are tailored based the signals received from the microenvironment such as those through proinflamatory cytokines and Danger- Associated Molecular Patterns (DAMPs) receptors. Once activated, MSC can modulate both innate and specific immune system in vitro. This is accomplished by inhibiting activation and proliferation of effector cells of myeloid (neutrophil, monocyte/macrophage, dendritic) and lymphoid (Th1, Th17, B, NK) lineages, as well as, by promoting differentiation and expansion of regulatory cells (Treg, M2 macrophages, and myeloid derived suppressor cells). In vivo immunomodulatory activities of MSC have been supported by the findings of increased Treg and decreased Th17 cells in several studies. Improvement of immune regulation coupled with tropism and angiogenesis is promising for MSC treatment allowing reparation of tissues damaged by inflammation.

FIGURE 3

Depicts some of the considerations and challenges with MSC treatment: Treatment regimens are usually based clinical considerations as listed in the first column, i.e., genetic influences and disease course as well as the history of treatment response and social concerns. Genetic and epigenetic factors (red arrows) and their environment (green arrows) are unique to each patient. These combined factors may result in immune dysregulation (blue arrows) and a subsequent adversary immune memory (gray arrows). Therapies (in green text box) are designed to dampen inflammation. In selected patients, personalized cell based treatment protocols can be introduced to improve long-term outcomes and minimize damage. New algorithms are needed based on data derived from expanded laboratory panels and real time assessment tools that are now available through adaptations of existing technology and essential for patient centered care.