The Editorial on the Research Topic
Searching for Immune Tolerance Manipulating New Molecules and Exploiting New Concepts
on Lymphocyte Biology
This research topic was inspired in those still non-curable inflammatory conditions,
such as autoimmune diseases and transplant rejection, based on the fact that immunologists
worldwide are still searching for strategies to restore long-term immune tolerance.
Thus, we gathered several researchers whom actively base their investigation lines
in novel molecules and immune cell populations that can be exploited to design new
strategies for the establishment or recovery of tolerance.
In the context of autoimmunity, intriguing is the role of interferon (IFN)-γ in the
pathogenesis of multiple sclerosis (MS) and its animal model, the experimental autoimmune
encephalomyelitis, which is reviewed in two articles contained in this edition (Ottum
et al.; Arellano et al.). They focus on new evidence that help to explain the seemingly
opposing effects of this cytokine over different central nervous system cells and
on different stages of the disease, giving some important clues that can help to guide
the potential therapeutic use of IFN-γ in MS patients. Other cytokine that recently
has been focus of interest is IL-33, a molecule first described as an alarmin, but
Gajardo-Carrasco et al. detail the plethora of now recognized functions in which IL-33
is involved, with special attention in T cell biology, adaptive immunity, tolerance,
and immunological disorders.
Continuing with an update on molecules with pivotal immune function, Le Mercier et
al. and Guo and Wang deliver us a solid snap shot on receptors and ligands with stimulatory
and inhibitory immune activity, revising both classic and newest members, their contribution
to disease and how they have been currently targeted to utilize them for therapeutic
purposes. Special attention received the new Ig family member VISTA, which is presented
as an interesting modulator of the immune response and with high potential for its
exploitation in the clinic.
Similarly, the article by Iruretagoyena et al. addresses the immune regulatory aspects
of vitamin D and its importance in controlling the development of autoimmune diseases.
This review has a particular emphasis on the participation of this vitamin in the
physiopathology of systemic lupus erythematosus (SLE) and gives an update on the latest
data about vitamin D supplementation in SLE patients.
Regarding the use of immune cells with therapeutic purposes, this research topic contains
five reviews that put the spotlight over the use of dendritic cells (DCs) and regulatory
T cells (Tregs) as tools to treat immune-related conditions (including autoimmunity
and transplant rejection). The article by Schinnerling et al. summarizes the recent
advances in the description of intracellular pathways and transcriptional regulators
that command the monocyte-derived tolerogenic human DCs differentiation program and
propose candidate molecules that could be regarded as key in their tolerogenic functions.
On the other hand, Maggi et al. examine one of the putative mechanisms of action of
tolerogenic DCs; this is the induction of hyporesponsive or anergic CD4+ T cells.
The authors review recent findings in the impact of CD4+ T cells anergy induction
in animal models of autoimmune diseases development and progression, and discuss on
the potential benefits of exploiting this mechanism for therapeutic purposes in humans.
Similarly, Osorio et al. present a complete revision on DCs nature, from their origin,
lineages, differentiation process, subtypes, and physiological role, linking these
observations with diseases and mentioning current technological approaches to use
them as a source for cellular therapy. On the other hand, Safinia et al. and Gregori
et al. targeted human Tregs, describing extensively all their phenotypic characteristics,
the different subpopulations identified to date based on certain surface markers and
their mechanisms to drive immune suppression, and compiling simultaneously all the
results from finished and ongoing clinical trials. In addition, both works discuss
different aspects of human Tregs clinical grade manufacture and the variables that
need to be improved to perfect the protocol, such as viability, antigen-specificity,
cell expansion efficiency, and phenotypic/functional stability.
In parallel, the original article by Ruiz et al. proposes a modified protocol to favor
mixed chimerism and further transplant acceptance in a preclinical model. Their novelty
bases in the use of antigen-specific Tregs generated in vitro in the presence of IL-2,
TGF-β, and retinoic acid (RA), in conjunction with previously established procedures
as non-myeloablative irradiation and administration of immunosuppressant drugs. This
group observed that the transfer of RA-Tregs facilitates donor-cells engraftment and
allows for the acceptance of skin allografts, proposing the inclusion of Tregs as
co-therapeutic tool. Another article reports how Soto et al. pinpoint at another cell
population, frequently overlooked when it comes to tolerance mechanisms: B cells.
Using systemic sclerosis (SSc) as a paradigmatic autoimmune disease with cellular
and humoral components, the authors describe alterations in the expression levels
of activator and inhibitor receptors on B cells from SSc patients that could contribute
with the hyperactivated phenotype of these cells. They also demonstrate that IL-10-producing
B cells and IL-10 secretion by stimulated B cells are reduced in SSc patients, which
can imply that these patients have an impaired anti-inflammatory function on regulatory
B cells, a subset specifically dedicated to promote tolerance to innocuous antigens.
The restoration of the capacity of these cells to express adequate levels of protolerogenic
molecules and regain their regulatory capability through novel or current B cell-targeted
therapies could be a promising therapy for SSc or related autoimmune diseases.
Finally, the review by Parigi et al. brings us to a different face of immune tolerance,
the one that keep us from mounting exacerbated immune responses against food antigens
and commensal microbiota. Disruptions of the tolerogenic mechanisms displayed by a
normal intestinal immune system can lead to severe conditions, such as food allergy
or inflammatory bowel diseases. This review deals with the way how diet, breast milk,
and solid food shape the immune system of newborns and defines the homeostasis in
the intestinal microenvironment, thus conferring risk or protection for the future
development of immune mediated diseases.
Overall, we achieved putting together a nice compilation on the current molecules
and cell populations that are being aggressively targeted to restore immune tolerance
in diseased patients. While many efforts are put in translational immunology, basic
science immunologists continue working to satisfy these goals.
DC wrote the editorial for this research topic. KP-L coordinated this research topic
and wrote the editorial.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial
or financial relationships that could be construed as a potential conflict of interest.