Page 44 - Power of Stem Cells- arthritis and regeneration

Luque-Campos et al. MSCs and Memory T Cells in RA

clinical trials including RA patients with an inadequate response the autoimmune diseases. In this context, exist 14 MSC-based
to methotrexate. The phase II clinical study on RA patients therapy clinical trials for RA. Upon them, it has been reported
demonstrated that the administration of brodalumab did not that the intravenous infusion of allogeneic bone marrow and
improve RA progression as revealed by the minimal response umbilical cord-derived MSC in a small group of refractory RA
criteria set designed by the American College of Rheumatology patients resistant to the anti-TNF monoclonal antibody therapy,
(ACR) (58). Similar results were observed after secukinumab led to a reduced erythrocyte sedimentation rate, improvement
administration in a phase Ib clinical study that included on DAS28 clinical score and diminished on the serum anti-
moderate to severe RA patients (59). Indeed, the administration cyclic citrullinated peptide (anti-CCP) antibody level, indicating
of these drugs did not reduce the frequency of memory Th17 the efficacy of MSC treatment. However, the observed clinical
cells. Interestingly, patients with RA treated with TNF inhibitors, improvement was only partial and temporary because of the short
possess pathogenic Th17 cells with a deleterious phenotype term follow-up (75). In another study, using allogeneic UC-MSCs
because of the high production of granulocyte-macrophage for RA treatment, the safety and effectiveness was demonstrated
colony-stimulating factor (GM-CSF) (57). Indeed, GM-CSF is in a larger number of patients (76). In this study, MSCs and
indispensable for the differentiation of inflammatory dendritic DMARDs were co-administrated intravenously in 172 patients
+
cells (infDCs) inducing the activation of memory CD4 T cells with active RA inducing a significant increase in the percentage
+
producing IL-17 (60, 61). Thus, a monoclonal antibody against of regulatory CD4 T cells (Treg) in the blood together with a
GM-CSF has been developed and described to be effective significant clinical improvement for up to 6 months. Moreover,
in clinical trial for RA treatment (62). However, despite this repeated infusion of MSCs after this period allowed an increased
promising result, the use of the anti-GM-CSF antibody has not therapeutic efficacy of the cells (76). More recently, in a phase
yet been approved (62). Ib/IIa clinical trial, the intravenous administration of allogeneic
Inhibitors of the Janus kinases (JAKs), such as Tofacitinib and expanded adipose-derived stem cells (ASCs) in a study that
Baricitinib, have also been developed for RA treatment (63, 64). included 53 patients with a placebo group was shown to be safe
These inhibitors block the activation of signal transducer and and well tolerated in refractory RA patients (77).
activator of transcription (STATs) signaling pathways, which Unfortunately at today there is no report that shows an
drive the signature of many cytokines including interleukin-7 immune-monitoring of RA patients after MSCs infusion that
(IL-7) and interleukin-15 (IL-15) that are important for memory could allow us to compare the immune profile of RA patients
T cells proliferation and survival (64–66). Another approach treated or not with MSCs with their clinical score before and
was the development of drugs that mimic mechanisms naturally after MSCs infusion. Indeed, it is mandatory to deepen on how
produced by our own immune system. For example, Abatacept MSCs affect the proinflammatory cells that are deregulated in
is a soluble recombinant human fusion protein comprising the these patients in particular pathogenic memory T cells. This
extracellular domain of human cytotoxic T-Lymphocyte Antigen information will surely help us to understand the mechanism by
4 (CTLA-4). This protein binds to CD80 and CD86 receptors on which MSCs exert their therapeutic function that will allows us
the antigen-presenting cells (APCs) and blocks the interaction to improve MSCs-based therapy.
with T cells through the co-stimulatory molecule CD28 (67).
Clinical trials have shown promising results using Abatacept for
RA treatment (68). However, a subset of tissue-infiltrating CD4 + IMMUNOMODULATORY ROLE OF MSCs
T cells from a group of RA patients have been shown to lose the ON MEMORY T CELLS: FOCUS ON RA
expression of CD28 while starting to express memory markers
(54, 69). These latter cells exhibit a high capacity to produce Despite the significant advances that have been made in the
pro-inflammatory cytokines such as interferon-gamma (IFNγ) generation of novel therapies against RA, there are still a lot
and TNFα and cytotoxic activity (69–73). Remarkably, the effect of patients that do not respond to any treatments. Hence it is
of bDMARD administration on memory T cell population has reasonable to think that the resistance of pathogenic memory T
never been addressed. cells could be the main contributor to the absence of a beneficial
Although a significant progress has been made with the effect of these immunomodulatory therapies (78, 79). Therefore,
current state of the art RA treatment for obtaining long- it is mandatory for the successfully development of RA therapies
term remission-induction, still between 20 and 30% of patients to target these specific T cells subsets. In this context, the effect
with moderate-to-severe RA do not positively respond to of MSCs on memory T cells have been investigated. For example,
mono or combinations therapy (plus Methotrexate) with these Pianta et al. demonstrated that the conditioned medium derived
agents (74) thus the development of novel therapies targeting from the mesenchymal layer of the human amniotic membrane
pathogenic memory T cells seems to be ideal to improve (CM-hAMSC) strongly inhibits central memory (CD45RO +
−
+
+
RA progression. CD62L ) as well as effector memory (CD45RO CD62L ) T cell
subsets, although the later ones to a lower extent (80). Also, using
MSC-Based Therapy for RA Treatment Peripheral Blood Mononuclear Cells (PBMC) activated with
Despite the fact that MSCs based therapy for RA treatment is phytohemagglutinin (PHA), it has been shown that MSCs highly
+
one of the main autoimmune disease model use to study the inhibit the proliferation of T CM , T EM , and effector CD4 T cells
mechanism underlying the therapeutic effect of MSCs, nowadays, (81). Moreover, Mareschi et al. observed that MSCs derived from
RA MSCs-based clinical trials has been the least studied within different tissues such as bone marrow and placenta were able to

Frontiers in Immunology | www.frontiersin.org 4 April 2019 | Volume 10 | Article 798