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in experimental autoimmune diseases: a central role of mycobacterial adjuvant-induced myelopoiesis
Laboratory of Immunobiology, Rega Institute, Katholieke Universiteit Leuven, Faculty of Medicine, Belgium
Correspondence: Dr. P. Matthys, Rega Institute, University of Leuven, Laboratory of Immunobiology, Minderbroedersstraat 10, B-3000 Leuven, Belgium. E-mail: Patrick.Matthys{at}rega.kuleuven.ac.be
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONIFN-{gamma} IN EXPERIMENTAL...IFN-{gamma}, MYCOBACTERIA, AND...PERSPECTIVESREFERENCES |
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(IFN-) has extensively been investigated by using
neutralizing anti-IFN- antibodies and by employing mice genetically
deficient in IFN- or its receptor. In these studies
disease-promoting as well as disease-protective roles of endogenous
IFN- have been described. Remarkably, in most models that rely on
the use of CFA, there is abundant evidence for a protective role. Here,
we review evidence that this role derives from an inhibitory effect of
IFN- on myelopoiesis elicited by the killed mycobacteria. These
findings explain the bimodal role of IFN- in different models of
autoimmune disease and raise questions regarding the clinical relevance
of these models.
Key Words: autoimmunity • Freund’s adjuvant • mycobacterium • hematopoiesis
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONIFN-{gamma} IN EXPERIMENTAL...IFN-{gamma}, MYCOBACTERIA, AND...PERSPECTIVESREFERENCES |
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(IFN-) in
in vivo models of autoimmune diseases. By employing
neutralizing antibodies or the gene knock-out approach, these studies
have invariably revealed dramatic effects of ablation of the IFN-
pathway. Remarkably, depending on the model under study or on the
experimental conditions imposed, disease-promoting as well as
disease-inhibiting roles were assigned to endogenous IFN-. Like all
cytokines, IFN- exerts diverse actions on many, if not all, types of
cells. These actions of IFN- and the interactions with other
cytokines have allowed construction of a conceptual framework
accommodating most disease-promoting in vivo effects.
However, proposed mechanism(s) underlying disease-inhibitory roles of
IFN- in autoimmune pathogenesis could until recently not
convincingly be substantiated. Here we briefly review the role of
IFN- in models of autoimmune pathogenesis and we argue that the
disease-inhibitory role that it plays in most of these models is
related to the use of Freund’s complete adjuvant, and derives from the
inhibitory effect of IFN- on myelopoiesis, in particular the
generation of a Mac-1+ cell population. |
IFN- IN EXPERIMENTAL AUTOIMMUNITY
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is among the main signal molecules by which lymphocytes
regulate inflammatory effector cells, in particular mononuclear
phagocytes (MPC) and endothelial cells (EC) [for a general review see
ref. 1 ]. It is a typical lymphokine, being produced almost exclusively
by natural killer (NK) cells in the aspecific phases, and by activated
CD4+ Th1 and CD8+ cells in the antigen-specific
phases of immune responses. Receptors for IFN- are constitutively
expressed not only on MPCs and ECs, but in fact on virtually all cell
types, so that not a single organ or organ system escapes the action of
IFN- reaching the bloodstream.
The role of endogenous IFN- in animal models of autoimmune disease
has been evaluated by studying alterations in disease course by
administration of anti-IFN- antibodies, by IFN- or IFN-
receptor gene knock-out, or by overexpression of IFN- in transgenic
mice. In each model the outcome of these interventions has invariably
been indicative of a crucial role of IFN- in autoimmune
pathogenesis; in some models as an overall disease promoter and in
others as an overall disease-limiting factor. An overview of the
IFN- ablation studies is shown in Table 1
. Although the results have been clear-cut and reproducible, the
nature of the underlying mechanisms has remained largely inferential or
even speculative. The disease-promoting effects of endogenous IFN-
have been proposed to be due to its well-known stimulatory effects on
expression of MHC Class I or Class II molecules, co-stimulatory
molecules, or cell adhesion molecules, or on differentiation of B or T
lymphocytes, or on production of inflammatory mediators, such as tumor
necrosis factor 
(TNF-) or nitric oxide (NO) by macrophages (see
Table 2 ). For instance, in diabetes-prone NOD/Wehi mice, treatment with
anti-IFN- antibody reduced the incidence and severity of diabetes
and also prevents overexpression of MHC Class I antigen on islet and
infiltrating cells [2
3
4
]. In a transgenic model of
autoimmune diabetes, overexpression of IFN- in the islets of
Langerhans was found to result in their inflammatory destruction
[5
]; treatment of the mice with anti-IFN- antibody
halted progression of disease [6
]. Characteristic for
this model were the overexpression of MHC Class II molecules and cell
adhesion molecules on non-endocrine cells [7
]. Augmented
production of NO by up-regulation of inducible NO synthase is another
mechanism of pancreatic tissue injury inflicted by IFN-. Thus, it
was shown that IFN-, in concert with TNF, induces NO in mouse islet
cells in vitro and that accompanying cytotoxicity can be
prevented by an inhibitor of inducible nitric oxide synthase (iNOS)
[8
]. Similarly, in cultured human pancreatic ductal
cells, combined treatment with interleukin-1ß (IL-1ß) and IFN-
augmented expression of iNOS and production of NO [9
].
Stimulatory effects of IFN- on antibody formation have been invoked
to explain its role in models of myasthenia gravis [10
,
11
] and in lupus [12
], both prototype
Th2-associated autoimmune diseases. In both models auto-antibody
production was shown to depend on IFN-.
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exerts a disease-limiting
effect, possible explanations have been much less obvious. The seminal
example is experimental autoimmune encephalomyelitis (EAE). Here,
administration of anti-IFN- antibody or ablation of the IFN-
ligand or the IFN-R gene results in higher disease scores
[13
14
15
16
17
18
19
]. Yet, EAE is nothing less than the prototype of
an autoimmune disease in which the organ lesions result from a
delayed-type hypersensitivity (DTH) inflammatory reaction elicited by
auto-antigen-specific CD4+ T cells of the IFN--secreting
Th1 type. The disease is transferable by such cells, and expression of
IFN- in the central nervous system (CNS) coincides with disease
manifestations and correlates with disease severity. To explain this
paradox, we and others [13
, 20
] have
proposed a model in which IFN- exerts opposing effects at the local
and at the systemic level. Locally, IFN- would play its normal
pro-inflammatory role, while at the systemic level it would exert
immunomodulatory effects that tend to protect against disease. Evidence
in support of a disease-promoting potential of locally produced IFN-
comes from the observation that administration of IFN- in the brain
[21
] or in the spinal cord [22
] causes by
itself recruitment of leukocytes to the CNS. Intrathecal injection of
IFN- was also reported to potentiate anti-MOG antibody-mediated
demyelination in rats [23
]. In mice, a pro-inflammatory
role of locally produced IFN- is apparent from the observations with
transgenic mice [24
25
26
]. Thus, mice generated to
overexpress IFN- by using an oligodendrocyte-specific promoter
spontaneously developed demyelination and clinical symptoms consistent
with a CNS disorder [24
, 25
]. In another
study, mice overexpressing IFN- in oligodendrocytes, although not
developing spontaneous CNS inflammation or not being oversensitive to
induction of EAE, did develop a more protracted form of the disease
[26
]. The mechanisms by which IFN- exerts a local
disease-promoting role in the CNS have received ample consideration in
the literature: induction of MHC molecule expression and activation of
glial and endothelial cells are the most salient ones.
In recognition of the fact that EAE involves not only local
immunocompetent cells in the CNS, but also (or perhaps even more so) in
the spleen and lymph nodes, it has been proposed [13
,
20
] that in these organs IFN- would trigger an
immunosuppressive or anti-inflammatory pathway that supersedes the
local pro-inflammatory effect. The target for suppression is the
generation of encephalitogenic T cell clones or their passage into the
CNS. Intervention of secondary IFN--induced factors [e.g.,
transforming growth factor ß (TGF-ß)] to explain immunosuppression
has been invoked [15
]. That there exist
IFN--dependent suppressive pathways is evident from studies in model
systems for other diseases, in particular chronic infection with
Trypanosomes or Mycobacteria [reviewed in ref. 1
]. Studies to
elucidate the nature of these IFN--dependent suppressive circuits
have pinpointed an MPC-like cell as a mediator. A downstream
immunosuppressive effector molecule might be NO, well known to be
induced by IFN- and to be endowed with strong modulatory effects on
inflammation. Numerous studies on the role of NO in EAE have been
reported, mostly relying on the use of inhibitors of NO synthases.
These studies, as reviewed previously [27
], have
suggested the existence of NO-mediated disease-promoting as well as
protective pathways. One model holds that NO, produced during the
induction phase of EAE, exerts a protective effect by inhibiting T cell
proliferation [28
, 29
].
Recently, evidence has come forward that IFN- can down-regulate EAE
pathogenesis not only by acting at the systemic but also at the local
level. Working with adoptively transferred EAE in radiation-conditioned
bone marrow chimeras between IFN-R-deficient and wild-type mice,
Willenborg et al. [29
] found that the disease pattern in
both types of chimeras was identical to that in plain
IFN-R-deficient mice, because it was characterized by failure to
recover from the primary attack. Because in IFN-R-deficient
recipient chimeras the CNS target cells were unresponsive to IFN-,
whereas the peripheral lymphoid cells were wild-type and duly
responsive to IFN-, the authors concluded that the down-modulatory
effect of endogenous IFN- results at least in part from an effect on
local CNS cells.
Also, Tran et al. [30
] reported that IFN-R- or
IFN- ligand-ablated mice, when induced with auto-antigen in CFA to
develop EAE, display a pattern of chemokine mRNA expression in the CNS,
which differs from that in the CNS of wild-type mice by absence of
RANTES and MCP-1 and overexpression of MIP-2 and TCAG-3 (T cell
activation gene-3), both neutrophil-attracting chemokines. Thus, a
local effect of IFN- would consist of favoring infiltration by
mononuclear phagocytes rather than neutrophils.
MECHANISM OF THE DISEASE-LIMITING ROLE OF IFN- IN AUTOIMMUNE
ARTHRITIS
IFN- plays a disease-limiting role not only in EAE, but also in
EAU [20
, 31
, 32
] and CIA
[33
34
35
]. In CIA and EAU the increased incidence and
severity of disease which follows ablation of IFN- is associated
with increased cutaneous DTH reactivity toward autoantigen
[20
, 33
]. Similarly, in a classical model
of cutaneous DTH reaction against a completely foreign antigen,
in vivo blockage of IFN- has been shown to augment rather
than to inhibit leukocyte influx in the skin [36
]. Thus,
in vivo augmentation of DTH reactivity by blockage of
IFN- is a general phenomenon in mice. Experimental protocols for
induction of DTH as well as those used for induction of autoimmune
disease most often rely on CFA as a vehicle for the antigen. CFA
contains dead mycobacteria, which act as strong immunostimulants.
Although the mechanism of their action is not well understood, it is
known that they persist for a long time in the body. Production of
IFN- is a critical factor in host defense toward viable mycobacteria
[37
, 38
]. Therefore, IFN- may also play
a role in elimination of the dead mycobacteria and this might provide a
clue to explain why IFN- plays a protective role in autoimmune
disease models relying on the use of CFA. To test this possibility we
tried and succeeded in inducing CIA using Freund’s adjuvant without
added killed mycobacteria. The arthritis developing in mice immunized
with collagen II in IFA had all the characteristics of classical CIA
induced by collagen II in CFA, except that it failed to develop in
IFN-R KO mice, whereas such mice develop more severe CIA when it is
induced by the aid of mycobacteria-containing CFA [33
].
Thus, omission of mycobacteria inverts the role of endogenous IFN-
to a disease-promoting factor, indicating that the mycobacterial
component of CFA opens a pathway by which endogenous IFN- exerts a
protective effect that supersedes its otherwise disease-promoting
effect.
Augmented disease activity in the IFN-R-deficient mice, when
mycobacteria are present in the adjuvant, is mainly due to an increased
effector function of cellular rather than humoral immunity. Indeed, in
IFN-R KO mice given the IFA-assisted induction schedule, both the
antibody and the cutaneous DTH response to collagen II are lower than
in the wild-types [33
]. With the CFA-assisted induction
schedule the antibody response is still reduced in IFN-R KO mice but
their DTH response is dramatically increased. Hence it appears that the
disease-limiting effect of IFN- concerns the induction or effector
phases of DTH rather than those of the humoral response. The clue to
the nature of the effect comes from events in the peripheral
hematopoietic system. When mycobacteria-containing CFA is used as
adjuvant for disease induction, splenomegaly with augmented proportions
immature and mature cells of the monocyte-macrophage and granulocytic
lineages (all are Mac-1+) develops. This
hematopoietic remodeling is more pronounced in IFN-R KO than in
wild-type mice and the expansion of Mac-1+ cells correlates
in time with the disease symptoms [33
].
Mac-1+ mononuclear phagocytes are amongst the effectors of
the DTH reaction, and their dramatically increased number in IFN-R
KO mice indicates that IFN- somehow controls their expansion and
thereby limits disease development in the classical CIA model in which
mycobacteria are used as adjuvant.
The bimodal action of IFN- in CIA thus consists of inhibiting
the generation of myeloid cells from extramedullary myelopoiesis, on
the one hand, and activating the MPCs resulting from such myelopoiesis
on the other hand. In the absence of mycobacteria, myelopoiesis is of
less importance for disease development, so that the MPC-activating
effect of IFN- as well as autoantigen-specific reactivity of T and B
cells are the predominant factors. In the presence of mycobacteria,
myelopoiesis becomes the more important factor for disease severity,
and its inhibition by IFN- results in a disease-limiting effect
(Fig. 1
). In other terms: not only the state of activation of the effector
MPCs is of importance but also their number.
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IFN-, MYCOBACTERIA, AND MYELOPOIESIS
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TOPABSTRACTINTRODUCTIONIFN-{gamma} IN EXPERIMENTAL...IFN-{gamma}, MYCOBACTERIA, AND...PERSPECTIVESREFERENCES |
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inhibit Mac-1+ myelopoiesis? Two
possible pathways may be considered (Fig. 1)
: IFN- may directly
affect progenitor cells and inhibit their proliferation, or it may
reduce the stimulus for myelopoiesis by accelerating the elimination of
the dead mycobacterial cells from the body. Direct inhibitory effects
of IFN- on hematopoiesis have been documented in several systems.
The stimulatory effect of IL-12 on hematopoiesis was reported to be
counteracted by IFN- [39
], and production of CSF-1 by
monocytes was found to be inhibited by IFN- [40
]. Of
special relevance for the second alternative is a study demonstrating a
dramatic effect of the IFN- KO mutation on hematopoietic remodeling
during infection with Mycobacterium tuberculosis BCG. The
normal splenic architecture of the IFN- KO mice was found to be
effaced by expanding myeloid cells [41
]. A similar
process may take place in IFN-R KO mice, which receive immunization
schedules employing killed mycobacteria as a component of CFA.
Macrophages of IFN--deficient mice may perform poorly in destroying
the mycobacterial cell bodies. This may result in long-term persistence
of these bodies in the lymphoid system and hence also in persistent
stimulation of hematopoietic cytokines. Most likely, both direct and
indirect mechanisms are involved: IFN- may well accelerate
elimination of the mycobacterial stimulants and at the same time
interfere with the hematopoietic cytokines released as a result of the
presence of the mycobacteria. Two of those cytokines, IL-6 and IL-12,
were considered in our study on CIA [33
]. We found that
treatment of the mice with neutralizing anti-IL-6 or anti-IL-12
antibodies inhibited both the expansion of the Mac-1+ cell
population and the development of arthritis. IL-6 is known to synergize
with IL-3 (multi-CSF) in supporting the formation of multilineage blast
cell colonies in murine spleen cell cultures, and also to stimulate
differentiation of myeloid cell lines into macrophage- and
granulocyte-like cells [for review see ref. 42
]. IL-12 also affects
hematopoiesis. Specifically, in IFN-R KO mice, IL-12 administration
caused rather increased bone marrow hematopoiesis and strong
extramedullary hematopoiesis in the spleen [39
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PERSPECTIVES |
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TOPABSTRACTINTRODUCTIONIFN-{gamma} IN EXPERIMENTAL...IFN-{gamma}, MYCOBACTERIA, AND...PERSPECTIVESREFERENCES |
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has the potential to
influence DTH-dependent autoimmune disease in two directions. Aside
from its classical pro-inflammatory effect through activation of MPCs,
B cells, and ECs, it may exert a disease-limiting effect by inhibiting
myelopoiesis. The latter may supersede the former in systems in which
myelopoiesis is extremely prominent as a disease determinant. This
model for explaining the bimodal role of IFN- in autoimmune disease
opens interesting perspectives and raises new research questions.
Other autoimmune diseases
Is the inhibiting effect of IFN- on CFA-induced hematopoiesis
operational in other autoimmune diseases? From the overview presented
in Table 1
it appears that all models in which a disease-limiting role
of IFN- has been noted rely on the use of CFA: EAE, EAU, CIA, and
autoimmune nephritis. It is important to note that in all of these
models, a more extensive infiltration of monocytes/macrophages and/or
neutrophils in the inflammatory lesions and an increased DTH to the
autoantigen were found in the IFN-R or ligand KO mice in comparison
with wild-type counterparts. In analogy with the situation of CIA, an
IFN--mediated immunosuppressive/anti-inflammatory circuit in these
models might be the down-regulation of the CFA-induced
Mac-1+ cell myelopoiesis.
However, there are some caveats. Of the models in which IFN-
promotes rather than counteracts disease, MG and EAT do rely on the use
of CFA. Mice deficient in expressing IFN- or its receptor were
clearly less susceptible to MG induction. However, in this model,
unlike in EAE, EAU, and nephritis, the disease manifestations are due
not to DTH-mediated tissue damage, but to binding of the acetylcholine
receptor by autoantibody. The other exception, EAT, is a special case.
Treatment with anti-IFN- antibody [43
] or ablation of
the IFN- receptor [44
] both reduced disease severity,
but without completely blocking it. In fact, in IFN-R KO mice the
disease manifestations occurred earlier, but also subsided earlier
after having reached lower peak levels. Thus, in this case, there is a
mixed disease-promoting and -inhibitory effect of IFN-. The main
mechanism of tissue damage in this model seems to derive from the
presence of large numbers of thyroglobulin-specific CD8+
cytolytic cells and high levels of anti-thyroglobulin antibody. Both
were reduced in anti-IFN- antibody-treated or IFN-R KO mice. This
may explain the lower overall severity. However, the earlier onset
should derive from another mechanism, possibly related to the use of
CFA and a role for myelopoiesis.
Hence, inhibition of myelopoiesis as a mechanism by which IFN- plays
a protective role seems not to apply to models in which autoantibody is
the principal pathogenetic pathway. But what can be said about models
that do not rely on mycobacterial adjuvant, such as lupus models or
autoimmune diabetes? The fact that, in these models, IFN- acts as a
disease promoter may be indicative of a predominant role of
autoantibody (lupus?), or of non-involvement of myelopoiesis
(diabetes?).
Is myelopoiesis an important factor in EAE? The observation that in
CIA, IFN- exerts an immunosuppressive/anti-inflammatory effect by
down-regulating CFA-induced Mac-1+ cell myelopoiesis
invites speculation that the same may indeed be true in actively
induced murine EAE. Mac-1+ cells have been shown to play a
role in regulating the invasion of autoreactive T cells in the CNS of
mice with EAE [45
]. However, experiments similar to
those which allowed documentation of the inhibitory effect of IFN-
on Mac-1+ cell myelopoiesis in CIA, could so far not be
done in EAE. Whereas the use of CFA is only a relative requirement in
CIA, it is an absolute one in actively induced murine EAE. We found no
published records of active induction of EAE in mice without the use of
CFA, and our attempts to omit CFA always resulted in total absence of
symptoms, making it operationally impossible to still lower the disease
score by ablating IFN- action. However, we could verify that a
myelopoietic burst similar to that seen in CIA does occur in mice with
EAE at about the time that symptoms appear [unpublished
observations]. In fact, this myelopoietic burst, as evident from
increased populations of immature and mature monocytes and neutrophils,
is also seen in mice receiving only CFA without other added antigens,
and it is dramatically more pronounced in IFN-R KO mice. It is
therefore reasonable to propose that the massive infiltration of
macrophages and granulocytes in the CNS of IFN--ablated mice with
EAE (Table 1) results at least in part from the absence of the
down-regulatory effect of IFN- on CFA-induced myelopoiesis. The
evidence for a disease-limiting role of endogenous IFN- in actively
induced EAE, as abundantly described (see above), is seemingly
contradicted by the recent study of Renno et al. [26
],
who described a more protracted form of EAE, elicited with MBP in CFA,
in mice overexpressing IFN- in the CNS. A possible explanation may
be that the IFN- levels in the circulation of these transgenic mice
were insufficient to inhibit myelopoiesis, although sufficient at the
local level to enhance CNS inflammation.
Another problem is the finding that IFN- ablation causes increased
disease severity also in a model of adoptively induced EAE, in which
the recipient mice did not receive CFA [15
,
16
]. However, in these experiments, the donor mice did
receive CFA, and the transferred cell population consisted of
unpurified lymph node cells containing not only encephalitogenic T
cells, but possibly also cells of the myeloid lineage, some of which
may even have contained mycobacteria. Therefore, indirect involvement
of mycobacteria in the effect of IFN- ablation in adoptive EAE can
at present not formally be excluded. Because adoptive transfer of EAE
can be performed with pure CD4+ T cells or with cloned
encephalitogenic T cell lines, it will be of interest to use these
systems for reevaluation of this question.
New aspects in the mode of action of CFA
The crucial position taken by myelopoiesis in the interplay
between mycobacterial adjuvant and IFN- as determinants of
DTH-dependent autoimmune disease throws new light on the exact role of
CFA. In particular, it emphasizes its role as a stimulant of a-specific
elements (phagocytes) and de-emphasizes its role as a stimulant of
(auto-)antigen-specific elements (T lymphocytes).
The use of Freund’s adjuvant as an instrument to induce experimental
autoimmune diseases dates back to the late 1940s and early 1950s when
models such as EAE were first described [46
]. Since
then, investigators have used CFA in their induction protocols without
being overly concerned about its mode of action. On the basis of early
studies examining adjuvant activity for immunization against foreign
antigens [47
], it was assumed that two mechanisms were
at play: (1) slow and protracted release of the water-soluble antigen
from the water-in-oil emulsion, and (2) overall stimulation of the
immune system by the mycobacterial component. Because mycobacteria, as
intracellular agents, are paradigmatically associated with Th1-directed
differentiation of T lymphocytes, it has also been inferred that
protocols using CFA lead to Th1 differentiation and cell-mediated
hypersensitivity, whereas those using IFA lead to antibody-mediated
forms of hypersensitivity [48
]. While this may be so,
the Th1/Th2 paradigm nevertheless falls short of providing an
explanation for the protective effect of IFN- in DTH-dependent
autoimmune diseases. Clearly, the well-known enhancing effect of CFA on
disease severity in these models derives more from enhancement of
Mac-1+ myelopoiesis than from Th1-directed derivation of T
lymphocyte differentiation.
Although immunologists are familiar with the splenomegaly developing
after immunization of animals with antigens in CFA, virtually no
studies have been done to document this in detail or to analyze it
mechanistically. In the 1960s and 1970s BCG was studied experimentally
and clinically for its ability to augment host defense against leukemia
and several other tumors. One aspect of the mode of action of BCG in
these systems was found to be its ability to enhance repopulation of
bone marrow and leukopoiesis after myeloablative chemotherapy
[49
]. In this context, treatment with BCG or CFA was
shown to cause increases in colony-forming units in bone marrow and in
levels of colony-stimulating factors in serum. More recently,
hematopoietic remodeling by BCG infection has been studied in more
detail and it was also shown that endogenous IFN- counteracts such
remodeling [41
].
Clinical implication: myelopoiesis, a target for therapy
The study of experimental autoimmune diseases aims at better
understanding of human diseases believed to be autoimmune in nature.
Not unexpectedly, however, the experimental models differ in certain
respects from their proposed natural human counterparts. The effect of
IFN- in EAE as a model for multiple sclerosis is a point in case:
the evidence that endogenous IFN- acts as a brake on development of
EAE disease manifestations is in sharp contrast to the observation that
treatment with IFN- elicits attacks in multiple sclerosis patients.
The evidence reviewed here suggests that the simple reason for this
discrepancy is the use, in EAE, of mycobacterial adjuvant, which
overemphasizes the role of myelopoiesis and thereby inverts the effect
of IFN-. Even so, myelopoiesis may still be a relatively important
factor in the pathogenesis of natural autoimmune diseases, as has been
suggested for rheumatoid arthritis [50
], and clinical
investigators may be well advised to take a closer look at it as a
possible target for therapeutic intervention.
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ACKNOWLEDGEMENTS |
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Received May 1, 2000; revised July 12, 2000; accepted July 25, 2000.
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REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONIFN-{gamma} IN EXPERIMENTAL...IFN-{gamma}, MYCOBACTERIA, AND...PERSPECTIVESREFERENCES |
|---|
: biology and role in pathogenesis Adv. Immunol. 62,61-130[Medline]
and interleukin-6 in autoimmune insulin-dependent diabetes in NOD/Wehi mice J. Clin. Invest. 87,739-742
J. Autoimmunity 4,237-248[Medline]
antibody Diabetologia 34,779-785[Medline]
Nature 346,844-847[Medline]
treatment prevents pancreatic inflammation in transgenic mice with ß-cell expression of interferon- J. Interferon. Res. 14,111-116[Medline]
transgenic mice J. Immunol. 152,4597-4603[Abstract]
plus tumor necrosis factor- Biochem. Biophys. Res. Commun. 197,22-27[Medline]
receptor deficiency are less susceptible to experimental autoimmune myasthenia gravis J. Immunol. 162,7335-7381 (IFN-) is necessary for the genesis of acetylcholine receptor-induced clinical experimental autoimmune Myasthenia gravis in mice J. Exp. Med. 186,385-391 receptor deletion prevents autoantibody production and glomerulonephritis in lupus-prone (NZBxNZW)F1 mice J. Immunol. 160,3713-3718 J. Immunol. 140,1506-1510[Abstract]
Eur. J. Immunol. 26,2393-2398[Medline]
monoclonal antibody treatment on the development of experimental allergic encephalomyelitis in resistant mouse strains J. Neuroimmunol. 53,101-107[Medline]
and anti-interleukin-2 monoclonal antibody treatment on the development of actively and passively induced experimental allergic encephalomyelitis in the SJL/J mouse J. Neuroimmunol. 36,105-115[Medline]
gene are susceptible to the induction of experimental autoimmune encephalomyelitis (EAE) J. Immunol. 156,5-7[Abstract]
confers resistance to experimental allergic encephalomyelitis Eur. J. Immunol. 26,1641-1646[Medline]
plays a critical down-regulatory role in the induction and effector phase of myelin oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis J. Immunol. 157,3223-3227[Abstract]
has a protective role against ocular autoimmunity in mice J. Immunol. 152,890-899[Abstract]
J. Neuroimmunol. 34,121-132[Medline]
potentiates antibody-mediated demyelination in vivo Ann. Neurol. 32,198-206[Medline]
in transgenic mice leads to hypomyelination, reactive gliosis, and abnormal cerebellar development Mol. Cell. Neurosci. 7,354-370[Medline]
Nature Med 3,1037-1041[Medline]
is critical to the control of murine autoimmune encephalomyelitis and regulates both in the periphery and in the target tissue: a possible role for nitric oxide J. Immunol. 163,5278-5286 shapes immune invasion of the central nervous system via regulation of chemokines J. Immunol. 164,2759-2768-deficient mice develop experimental autoimmune uveitis in the context of a deviant effector response J. Immunol. 158,5997-6005[Abstract]
at the systemic level protects mice against experimental autoimmune uveoretinitis Regional Immunol 6,153-155
receptor-deficient mice is conditioned by mycobacteria in Freund’s adjuvant and by increased expansion of Mac-1+ myeloid cells J. Immunol. 163,3503-3510 receptor-deficient mice J. Immunol. 158,5507-5513[Abstract]
receptors J. Immunol. 158,5501-5506[Abstract]
J. Immunol. 140,2889-2893
receptor Science 259,1742-1745 in resistance to Mycobacterium tuberculosis infection J. Exp. Med. 178,2249-2254 in vivo J. Exp. Med. 181,1893-1898-deficient mice infected with mycobacteria Blood 91,2914-2924 on experimental autoimmune thyroiditis (EAT): Prevention of disease and decrease of EAT-specific T cells Eur. J. Immunol. 23,275-278[Medline]
receptor gene Eur. J. Immunol. 28,201-208[Medline]
antibody J. Immunol. 149,2219[Abstract]
-deficient mice develop severe granulomatous experimental autoimmune thyroiditis with eosinophil infiltration in thyroids J. Immunol. 160,5105-5112-deficient mice J. Immunol. 163,2243-2248 (IFN-) during disease onset phase of murine experimental autoimmune orchitis. I. In vivo studies Clin. Exp. Immunol. 111,513-520[Medline]
is essential for the development of autoimmune glomerulonephritis in MRL/lpr mice J. Immunol. 158,5484-5491[Abstract]
receptor signalling is essential for the initiation, acceleration, and destruction of autoimmune kidney disease in MRL-Faslpr mice J. Immunol. 161,494-503 and interleukin-4 in murine lupus J. Clin. Invest. 99,1936-1946[Medline]
is required for lupus-like disease and lymphoaccumulation in MRL-lpr mice J. Clin. Invest. 101,364-371[Medline]
induces islet MHC antigens and enhances autoimmune, streptozotocin-induced diabetes in the mouse J. Immunol. 140,1111-1116[Abstract]
impacts at multiple points during the progression of autoimmune diabetes Proc. Natl. Acad. Sci. USA 94,13844-13849 is essential for destruction of ß-cells and development of insulin-dependent diabetes mellitus J. Exp. Med. 185,531-539This article has been cited by other articles:
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