Current Pharmaceutical Design, Volume 9, No. 3, 2003
Contents
Autoimmune Diseases
Executive
Editor: D. Stahl
Natural Killer T Cells as Targets for
Therapeutic Intervention in Autoimmune Diseases Pp.201-220
M.T.
Wilson and L. Van Kaer
Dendritic Cell Homeostasis in the Regulation
of Self-Reactivity
Pp.221-231
Burkhard
Ludewig, Philippe Krebs, Tobias Junt and Gennady Bocharov
Modulation of T Cell Immunity by TCR/pMHC
Dwell Time and Activating/Inhibitory Receptor Pairs on the Antigen-Presenting
Cell Pp.233-244
Alexis M. Kalergis
Regulation of Self-Reactive T Cells by Human
Immunoglobulins- Implications for Multiple Sclerosis Therapy Pp.245-256
Orhan Aktas and Frauke Zipp
Macrophages and the Regulation of
Self-Reactive T Cells
Pp.257-264
David H. Munn, and Andrew L. Mellor
Autoimmune Lymphoproliferative Syndrome
(ALPS) Pp.265-278
Jack J.H. Bleesing
Treatment of Refractory Autoimmune Diseases
with Ablative Immunotherapy Using Monoclonal Antibodies and/or High Dose
Chemotherapy with Hematopoietic Stem Cell Support Pp.279-288
Yossi
Cohen, Aaron Polliack, and Arnon Nagler
[Back to top] Natural Killer T Cells as Targets for
Therapeutic Intervention in Autoimmune Diseases
M.T.
Wilson and L. Van Kaer
Natural killer T (NKT) cells are a subset of lymphocytes that express
receptors characteristic of conventional T cells together with receptors
typically found on natural killer cells. A key feature of NKT cells is the
expression of a semi-invariant T cell receptor that is specific for glycolipid
antigens presented by the unusual major histocompatibility complex class I-like
molecule CD1d. While their precise immunological functions remain unknown, NKT
cells have been implicated in the regulation of adaptive immune responses,
including those directed against autoantigens. These findings raise the
possibility that specific stimulation of NKT cells may be exploited for
therapeutic purposes. A number of laboratories have tested this hypothesis,
utilizing the sea sponge-derived agent α-galactosylceramide
(α-GalCer), a specific agonist of NKT cells. Administration of
α-GalCer to mice results in potent activation of NKT cells, rapid and
robust cytokine production, and activation of a variety of cells of the innate
and adaptive immune systems. Most notably, repeated administration of
α-GalCer to mice favors the generation of conventional T lymphocytes
producing T helper (Th) type 2 cytokines such as IL-4 and IL-10. These findings
suggest that α-GalCer can modulate inflammatory conditions that are
mediated by pathogenic Th1 cells. Indeed, recent studies have demonstrated that
α-GalCer prevents the development of Type 1 diabetes in non-obese diabetic
mice and central nervous system inflammation in mouse models of multiple
sclerosis. Collectively, these studies provide a solid foundation for the
development of NKT cell ligands as pharmacological agents for treatment of
autoimmune diseases.
[Back to top] Dendritic Cell Homeostasis in the Regulation
of Self-Reactivity
Burkhard
Ludewig, Philippe Krebs, Tobias Junt and Gennady Bocharov
Dendritic cells (DC) are known for their remarkable ability to induce
specific T cell responses. However, the existing views on the role of DC in
maintaining tolerance to self-antigens and induction of autoimmunity are
somewhat controversial especially when the basic physiology of DC migration,
function and homeostasis is considered. This review attempts to provide a
comprehensive overview on these topics with particular emphasis on DC
homeostasis and presents implications for the generation of pathological
autoimmune T cell responses. Furthermore, we advocate the need for a conceptual
characterization of the immune system operating in vivo. With particular focus
on the contribution of DC, we suggest that a ‘spatiotemporal’ view of the rules
for T cell responses (antigen dose and availability, duration and mode of
antigen presentation) permits a better understanding of the relevant factors
contributing to the pathogenesis of autoimmune diseases.
[Back to top] Modulation of T Cell Immunity by TCR/pMHC
Dwell Time and Activating/Inhibitory Receptor Pairs on the Antigen-Presenting
Cell
Alexis
M. Kalergis
The molecular interactions occurring at the interface between the
antigen presenting cell (APC) and the T lymphocyte play an important role in
the immune surveillance against infectious agents and tumors, as well as in
autoimmunity and transplant rejection. The significance of the APC-T cell
interaction in immunity is underscored by the observation that deficiencies in
the function of either one of these two cell types cause extreme susceptibility
to infections and tumor growth. Furthermore, a disregulated APC-T cell
interaction can initiate autoimmunity. Thus, antigen recognition by T cells
must be tightly regulated in order to ensure protection against pathogens and
tumors, avoiding activation of self-reactive T cells. Efficient T cell
activation requires two simultaneous signals provided by the APC: Antigen (or
signal 1) and co-stimulation (or signal 2). The specificity of antigen
recognition by T cells (signal 1) is controlled exclusively by the T cell
receptor (TCR), an extremely diverse heterodimeric protein composed of
disulfide-bonded α and β chains. While it is clear that the TCR
recognizes antigens as small peptides bound to molecules of the Major
Histocompatibility Complex (MHC), the molecular explanation for the specificity
of antigen recognition by the αβTCR is just beginning to be
elucidated. In this review are described some of the advances made in the
understanding of the molecular interactions that define the antigen-specificity
of the TCR, and the current models for T cell activation by antigen on APCs are
discussed.
[Back to top] Regulation of Self-Reactive T Cells by Human
Immunoglobulins- Implications for Multiple Sclerosis Therapy
Orhan Aktas and Frauke Zipp
The intravenous administration of high doses of immunoglobulins pooled
from the plasma of healthy donors (IVIg therapy) has beneficial effects in
patients with a variety of autoimmune disorders. These clinical observations
indicate that IVIg have potent antiinflammatory characteristics, and
identification of the precise mode of action may open up perspectives for
future therapeutic strategies. In certain tissue-specific autoimmune disorders
like multiple sclerosis (MS), self-reactive T cells recognizing autoantigens
play a significant role for disease pathogenesis, as these cells are able to
initiate, maintain, and propagate the harmful immune attack in experimental
animal models of disease. These findings render self-reactive T cells an
important therapeutic target for autoimmune diseases.
Here, we review the effects of IVIg on the homeostasis of T cells and
discuss the possible therapeutic implications for multiple sclerosis. As
supported by several experimental studies, IVIg regulate crucial steps of T
cell-mediated immune responses. These effects involve the modulation of
activation, proliferation,
differentiation, apoptosis, and effector mechanisms of T cells. The
pattern of IVIg-T cell interactions is complex, as IVIg may directly bind to
regulatory structures on T cells, or modulate T cell functions indirectly via
soluble or cellular components of the immune system.
[Back to top] Macrophages and the Regulation of
Self-Reactive T Cells
David H. Munn, and Andrew L. Mellor
Macrophages are professional scavengers of apoptotic and necrotic
cells, and hence constantly take up self antigens. Paradoxically, macrophages
are also professional antigen-presenting cells, which would seem to invite
autoimmune disorders. Moreover, macrophages are effector cells in the
tissue-destruction phase of autoimmune disorders, where they encounter
additional self antigens in the stimulatory context of chronic inflammation.
This review examines the array of immunosuppressive mechanisms which may help
macrophages suppress unwanted T cell responses, and considers the consequences
of a breakdown in these negativeregulatory systems in autoimmunity.
[Back to top] Autoimmune Lymphoproliferative Syndrome
(ALPS)
Jack J.H. Bleesing
In patients with ALPS, defective homeostasis of lymphocytes is
reflected in abnormal accumulation of lymphocytes, leading to lymphadenopathy,
(hepato)splenomegaly and hypersplenism, autoimmunity due to a failure to remove
autoreactive lymphocytes, and inappropriate survival of lymphocytes associated
with an increased occurrence of lymphoma. Several of the laboratory findings
are unique for ALPS and reflect defective Fas-mediated apoptosis and abnormal
immune regulation. Much has been learned about the molecular mechanisms that
underlie defective Fas-mediated apoptosis and the complex relationship between
genotype, phenotype and disease penetrance. Family studies strongly suggest the
contribution of one or more additional factors to the pathogenesis of ALPS.
This may pertain to defective immunoregulation by an altered IL-2/IL-2 receptor
system, reflected in the specific loss of CD4+/CD25+ T cells, and/or by the
highly increased IL-10 levels, but other factors may equally be involved.
Treatment strategies remain mostly targeted at the disease manifestations, but
more specific therapies directed at the primary pathogenic defects themselves
might become possible in the future. Continued efforts directed at both careful
clinical follow-up and basic scientific investigation are needed to increase
our understanding of the incidence, natural history, and pathogenesis of ALPS.
In return, this may prove of benefit for the understanding of autoimmune
disease in general.
[Back to top] Treatment of Refractory Autoimmune Diseases with
Ablative Immunotherapy Using Monoclonal Antibodies and/or High Dose
Chemotherapy with Hematopoietic Stem Cell Support
Yossi
Cohen, Aaron Polliack, and Arnon Nagler
Immunological manipulations are the basis for modern treatments of
autoimmune diseases (AID). Targeted immune suppression with lymphopenic based
chemotherapy, and monoclonal anti B or T lymphocytic antibodies, are integral
part of the conditioning for stem cell transplantation (SCT). Immune
manipulation by Cyclophosphamide (Cy), ATG, Campath and recently rituximab
(RI), with or without stem cell support are the basis for emerging therapeutic
modalities aiming to eradicate the autoreactive clone in various autoimmune
disorders. Couple of hundreds of SCTs have been recently performed in various
autoimmune disorders, mainly multiple sclerosis (MS), progressive systemic
sclerosis (PSS), systemic lupus erythematosis (SLE) and rheumatoid arthritis
(RA). Preliminary results are encouraging. Better selection of patients and
earlier treatment, before irreversible organ failure develops will probably
improve results. Current ongoing multicenter studies are evaluating the role of
SCT in MS, RA, SLE, and PSS.