This paper describes the dendritic cell and its critical role in activation and suppression of immune responses.
The purpose of this paper is to review evidence for the ability of dendritic cells (DC) to
induce T cell activation or T cell tolerance with emphasize on cancer. DC are the most
potent of antigen presenting cells (APC), having the ability to activate naïve and memory
T cells about 100-fold higher than macrophages (1, 2). These functions have prompted
investigation of mechanisms by which DC promote immune responses, and how to use
these cells therapeutically. Conversely, DC have been shown to have a role in induction
of tolerance and clonal deletion (3). Classically, myeloid DC have been thought to
possess T cell stimulatory activity while lymphoid DC as being T cell suppressive and
responsible for negative selection in the thymus. While DC can be obtained by
differentiating CD34+ cells in culture (4), in vivo it is more likely that DC arise from
CD14+ monocytes differentiating into the myeloid subset (5), CD34 cells differentiating
directly into a circulating DC (5a) or a thymic precursor differentiating into a lymphoid
The concept of myeloid and lymphoid DC subsets is based on differential
functional characteristics, anatomical location, and surface marker expression between
the two types (7). Recent data suggests the division between these two subtypes may not
be clear cut (reviewed in 8). Evidence exists that myeloid derived DC which are CD8-
can be induced to express CD8 during maturation (9) and that a myeloid precursor can
give rise to both myeloid and lymphoid DC (10). One possibility is that DC lineages may
not be different entities but cells at different stages of maturation. However, in order to
have meaningful discussions, the myeloid and lymphoid lineages will be treated as
separate subsets based on surface marker expression. In the murine system, lymphoid
DC will be identified as DEC 205+, CD11b-, CD8+, while myeloid DC will be
characterized by the phenotype DEC 205-, CD11b+ (7). In the human system, the
identification scheme proposed by Faratian et al will be used, in which lymphoid DC are
CD4+, CD11c-, CD123+ (IL-3Rα), and myeloid DC are CD1a+, CD11c+, CD83+ (11).
Throughout the chapter, the term “immature” and “mature” DC will be used, this refers to DC of the myeloid lineage, since little is known about immature lymphoid DC.
T Cell Activation vs Tolerance
T cell activation is critical for immune responses to ensue. Such activation is usually
detected by the ability of the T cell to proliferate (CD4 T cell), induce cytotoxicity (CD8
T cell) or to secrete cytokines (both CD4 and CD8). T cell activation requires at least
two signals, one through the TCR and another through a costimulatory molecule such as
CD80 or CD86 on the APC. Activation through TCR alone will drive the cell into a state
of unresponsiveness termed anergy (12). Molecular mechanisms underlying the anergic
state are beyond the purpose of this essay but are discussed in the following references
(13, 14, 15). Anergic T cells can be taken out of their unresponsive state by
administration of the cytokine interleukin-2 (16). This observation provides rational for
the utilization of immune augmentative therapies in diseases, such as cancer, where
therapeutic gain may occur by activation of anergized T cells. Conversely, the ability of
T cells to exit a state of anergy provides opportunity for autoimmunity to arise by
breaking down of self tolerance through stimulation of autoreactive T cells.
Anergy of T cells may also be induced by crosslinking of inhibitory receptors on T cells.
One such receptor is CTLA-4 which binds with high affinity to CD80 and CD86 on the
APC. Recently, it was demonstrated that T cell inhibition through CTLA-4 can occur
through two mechanisms: intracellular signaling of the CTLA-4 molecule, and CTLA-4
blocking activation of CD28 on the T cell by virtue of competition for CD80 and CD86
While anergy implies T cell unresponsiveness, tolerance to an antigen may also come
about by death of the antigen-specific T cells. In an attempt to induce tolerance, Min et
al administered Fas ligand transfected donor DC into recipient mice receiving cardiac
allografts. Mice receiving transfected donor DC displayed prolonged graft survival only
when the DC were of donor origin (18). A naturally occurring example of tolerance
induced by T cell death is seen in pregnancy. Using H-Y-specific TCR transgenic mice,
Jiang et al demonstrated that maternal T cells specific for fetal antigens decrease in a
specific manner during pregnancy. This decrease was partially explained by the presence
of Fas ligand on the maternal cells in the placenta (19).
In order to provide a framework for understanding DC-T cell interactions several of the
main molecules on T cells responding to dendritic cells are listed in Table I.
Table I. T Cell Molecules Associated With Activation and Tolerance
Molecule Inducible (I)/Constitutive © Function Reference
CD28 C Costimulatory (12)
ICOS I Costimulatory (20)
CTLA-4 I Inhibitory (21)
CD30 I Inhibitory (22)
PD-1 I Inhibitory (23)
Fas I Death of T cell (24)
DR-4 C Death of T cell (25)
Activation of T cells by DC
The myeloid DC is exquisitely suited to act as the immune system’s watchtower against
invading pathogens. This type of DC has the capability to endocytose antigen in it’s
immature state, become partially activated by certain “danger signals” and home into the
lymph node where it becomes fully activated and presents antigens to T cells (26). DC
activitory signals could be heat shock proteins, bacterially derived products, debris from
dead cells and various molecular entities associated with tissue damage. The ability of
the DC to potently activate T cells is dependent on several key features the mature DC
a) Mature DC highly express MHC I and MHC II. These molecules contain peptide
antigens derived from the intracellular (cytosolic) and extracellular (endosomal)
compartments. The combination of MHC I-peptide, and MHC II-peptide can provide a
primary signal for activation of CD4 and CD8 T cells. The need for high levels of MHC
during antigen presentation is exemplified in experiments where expression of MHC II is
suppressed on APC by exogenous administration of CLIP, this results in weaker recall
response and ability to ameliorate autoimmune disease (27). In addition, DC have the
unique ability to acquire extracellular antigens, process them through the cytosolic
pathway, and present them on MHC I in order to activate CD8 T cell (28). This ability is
important in priming cytotoxic T cell responses to antigens which are present inside cells
that may not have the ability to activate the CD8 T cell by themselves. One example is
tumor antigens, which are in many cases intracellular. Most tumor cells have
deficiencies in TAP, low expression of MHC I, and absence of costimulatory molecules
such as CD80 or CD86 (29). This would be the tumor cell it’s self a poor stimulator of
CD8 T cells. Apoptotic bodies from tumor cells can be picked up by DC, processed by
the DC in the cytosolic pathway, and the DC can activate the tumor-specific CD8 cell
(30,31). Once the CD8 cells are activated by the DC, they can start to recognize the
tumor and induce an appropriate response.
b) Mature DC express costimulatory molecules. It is established that DC are the most
potent expressers of the costimulatory molecules CD80 and CD86 (2). However, a more
novel finding is that the costimulatory molecule CD86 is found in close apposition with
MHC I and MHC II inside the MIIC and CIIV compartments of immature and mature
DC, respectively (32). In the same study, confocal microscopy was utilized to examine
surface distribution of CD86 in comparison to MHC I and MHC II. All three molecules
seemed to be aggregated in raft-like structures. This was in contrast to the control surface
molecule, CD18, which was evenly distributed across the membrane. From this data it is
tempting to speculate that DC aggregate immunologically important molecules into
microdomains which may serve as counterparts for rafts and/or supermolecular activation
complexes (SMACs) on T cells (33).
Immature DC have been shown to express a costimulatory molecule, LIGHT, which is
the ligand for the herpesvirus entry mediator and lymphotoxin ß receptor found on T
cells. Blockade of LIGHT on DC during allogenic mixed lymphocyte reaction (MLR),
suppresses proliferation of responding T cells. Furthermore, exogenously administered
LIGHT can costimulated anti-CD3 induced proliferation in naïve T cells (34). The idea
of immature DC costimulating T cells is contradictory to findings, which will be
described below, that suggest immature DC are tolerogenic and inhibit MLR.
LIGHT is a member of the TNF-α superfamily. Several other costimulatory molecules
of this superfamily are found on DC. 4.1BB ligand (4.1BBL), is expressed on activated
DC and it’s receptor, 4.1BB, is found on activated T cells. Gramaglia et al showed that
in pigeon cytochrome c-pulsed fibroblasts, transfection with 4.1BBL was as effective at
stimulating proliferation of T cells as transfection with CD80 (35). The importance of
costimulation through 4.1BB in vivo was demonstrated in two models of highly
aggressive cancers where administration of crosslinking anti-body to 4.1 BB was able to
induce effective immune recognition and destruction of established murine tumors (36).
OX-40 ligand (OX-40L) is a member of the TNF-α superfamily which is expressed on
DC and can activate T cells to proliferate and secrete cytokines by binding to OX-40
(37). Crosslinking of CD3 can induce proliferation of T cells from a CD28 knockout
mouse when OX-40L is added, thus indicating costimulation can occur in absence of
Suppression of T cells by Lymphoid DC
Lymphoid DC are important for negative selection of autoreactive T cells in the thymus.
This as been demonstrated using an transgenic system in which MHC class II I-E
molecules were specifically target to DC by placing the gene under control of the CD11c
promoter. This approach demonstrated that I-E expression on thymic DC was sufficient
to negatively select I-E reactive CD4+ T cells (3). The ability of thymic DC to induce
tolerance to antigen has been demonstrated in an animal model of autoimmunity. Khoury
et al protected rats from onset of experimental allergic encephalomyelitis (EAE) by
intravenous injection of thymic DC pulsed with peptides from the autoantigen myelin
basic protein (MBP) (39).
Lymphoid DC can also be found in peripheral organs such as the spleen and liver based
on expression of DEC 205+, CD11b-, CD8+, in the mouse or CD4+, CD11c-, CD123+ (IL-3Rα) in the human. Hepatic allografts in mice have a comparatively longer survival than other organs. This has been attributed in part to the high proportion of resident lymphoid DC (40, 41). Liver derived lymphoid DC, in contrast to bone marrow derived myeloid DC induce production of the tolerance promoting cytokines IL-4 and IL-10 in T cells (42). Unfortunately, a successful strategy for expansion of these DC is lacking. An
attempt at such an expansion was made by systemic administration of the DC expanding
factor, Flt-3 ligand, to donor mice. Instead of promoting tolerance the grafts were
rejected at an accelerated rate (43).
Three mechanisms of lymphoid DC-induced tolerance:
a) Expression of Fas ligand (FasL). Activated T cells express the Fas receptor which
allows them to undergo activation-induced cell death. The importance of this receptor is
seen in a mouse strain, lpr, which develops autoimmunity and hyperproliferation of T
cells (44). Splenic lymphoid DC have been demonstrated to kill activated CD4 T cells
through expression of FasL (45). The relevance of this finding to DC biology remains to
be confirmed in other systems. However, as described above, the transfection of myeloid
DC with FasL can antigen-specifically prolong allograft acceptance (18). Therefore
further studies in this area are needed.
b) Suppression of IL-2 production. Kronin et al demonstrated that splenic lymphoid
DC are poor stimulators of MLR for CD8 cells. This was not attributed to FasL
expression on the DC but by the ability of the DC to block IL-2 production from the T
cell. No mechanism was proposed (46).
c) Expression of inhibitory receptors. It has been demonstrated for many years that
portal vein infusion of donor-specific lymphocytes prolongs renal allograft survival. A
molecule identified on lymphoid dendritic cells, OX-2, is speculated to be the cause for
this tolerogenic effect (47, 48). Administration of blocking antibodies to OX-2 inhibits
the ability of donor-specific lymphocytes to prolonged allograft survival (49). In the
same study it was demonstrated that infusion of donor lymphocytes into the portal vein
was associated with increased levels of IL-10 mRNA in the graft, but this was abrogated
by administration of the anti-OX-2 antibody. The OX-2 knockout mouse is susceptible to
collagen induced arthritis and EAE, thus hinting that this molecule may be important for
maintaining of self tolerance (50). In a personal communication, Grant McFadden stated
myxoma poxvirus contains an OX-2 homologue which is essential for virulence. Could
lymphoid dendritic cells possess such potent immune suppressor molecules that even
viruses would want to steal them?
Suppression of T cells by Myeloid DC
An example for the immunologically importance of immature DC is in cancer. Studies
by Rita Young have shown that several murine tumors produce systemic amounts of GMCSF (51, 52) and that administration of blocking antibody to GM-CSF could abrogate tumor-induced immune suppression (53). The mechanism of GM-CSF-induced immune suppression was production of IL-10, TGF-β, and nitric oxide from the immature DC (53a). GM-CSF given to bone marrow cells at low quantities in vitro, in the absence of IL-4, has been demonstrated to cause expansion of immature myeloid DC which promote allograft tolerance (54). These immature DC express low levels of CD80 and CD86, which may in part account for their ability to induce tolerance. Production of GM-CSF has been recently demonstrated in a battery of human tumor cell lines and this has been postulated by Bronte et al to be responsible for suppression of CD8 cytotoxic T cells seen in cancer bearing mice and patients (55).
Immature myeloid DC have been found in circulation of cancer patients, the number of
DC positively correlating with disease stage (56). These DC inhibit T cell proliferation
in an antigen-nonspecific manner, through mechanisms which remain to be elucidated.
Presence of these DCs is dependent on tumor size, since after surgical resection of tumors
their numbers drop (57). Immature circulating DC are also dependent on the
angiogenesis promoting protein vascular endothelial growth factor (VEGF). When
antibody to VEGF is administered clinically, the number of circulating immature DC
drops. Administration of anti-VEGF antibody to murine models of cancer increases the
ability of DC to activate T cell responses and induce tumor clearance (58).
Another system in which DC are tolerance promoting is the ultraviolet B (UVB) light
treated skin Langerhans cells (which are a type of myeloid DC that resides in the dermis).
These cells are capable of inactivating T cells or skewing their response to a tolerogenic
Th2 profile (reviewed in 59). Irradiation of murine Langerhans cells in vitro led the their
inability to present keyhole limpet hemocyanin (KLH) to Ag-specific, H2d restricted Th1
clones, but not to Th2 clones with the same specificity (60). Immunization of mice with
antigen at the site of UVB irradiation leads to induction of antigen-specific tolerance
(61). A postulated mechanism was that UV-treated APC stimulate activation of T
regulatory cells which kill DC through a Fas-dependent manner. UVB-treated DC
secrete an IL-12 antagonistic protein, the IL-12 p40 homodimer which can block the
ability of splenocytes to secrete IFN-γ after treatment with naturally occurring IL-12 (62).
In another system, DC which can not secrete agonistic IL-12 (generated in the presence
of prostaglandin E2 (PGE-2)) prime naïve human T cells to secrete the Th2 cytokines IL-
4 and IL-5, but can not prime secretion of Th1 cytokines such as IL-2, IFN-γ (63).
Chemically, the mechanism by which UVB radiation programs DC to promote
tolerogenic responses is postulated to involve the transformation of urocanic acid from its
nonimmunomodulatory trans-isoform to its immunosuppressive cis-isoform in the skin
strateum corneum (64, 65). Administration of antibody specific to the cis-isoform of
uraconic acid blocked the ability of UVB to suppress the MLR stimulating ability of
Langerhans cells derived from C3H mice (66).
Another method by which DC can inhibit activation of T cells and/or induce tolerance is
through metabolism of the amino acid tryptophan by the enzyme indoleamine 2,3-
dioxygenase (IDO). Since T cell proliferation and activation is highly dependent on
tryptophan, depletion of this amino acid can result in inhibit of T cell function. Munn et
al demonstrated that administration of an IDO-specific inhibitor, 1-methyl-tryptophan, to
allogenically pregnant mice resulted in rapid onset of immunologically mediated
abortion, thus suggesting expression of IDO may be required for maintaining tolerance to
the fetal allograft (67). IDO expression has been found on IFN-γ or T cell activated
human myeloid DC and administration of IDO-inhibitors to these activated DC can
augment their ability to stimulate T cell proliferation (68). Furthermore, abrogation of
the T cell suppressive effects of murine lymphoid DC by artificial ligation of CD40,
results in downregulation of their ability to degrade tryptophan (69).
From this point of the essay and onward, the term “DC” will refer to myeloid DC, since
the experiments described are recent and have not been performed in the lympoid lineage.
Indirect Activation of T cells by DC
The DC can condition the local immunological environment by virtue of stimulating
other cell types in order to facility activation of T cells. One example of such
conditioning is the ability of DC to activate NK cells. In an early study, it was
demonstrated monocytes can expand IL-2-induced NK cell numbers and augment
cytotoxicity (70). Since monocytes are precursors of myeloid DC, Fernandez et al
investigated whether culturing of monocyte-derived DC can stimulate NK cytotoxicity in
vitro. NK cells were endowed with potent tumor-cytolytic activity and IFN-γ synthesis
after coculture with DC in a contact-dependent manner. Furthermore, when both
monocyte-derived DC and Flt-3L-expanded DC were able to induce NK-dependent
antitumor effects in vivo (71). DC activation of NK cells derived from CD34+ cord
blood progenitors was demonstrated to occur via secretion of IL-12 and IL-18 by DC
(72). The possibility of NK activation by DC is particularly interesting in light of recent
observations that human and murine NK cells can be activated by cells expressing CD80
and/or CD86, in a CD28 independent manner (73,74). NK cells can increase the number
of activated T cells by secretion of immunomodulators such as IFN-γ (review in 75).
Another mechanism by which DC may indirectly augment activation of T cells is through
activation of NKT cells. These cells are potent producers of the cytokines IL-4 and IFN-
γ in response to activation of their conserved TCR, Vα14 Jα281 (murine) or Vα24Vβ11
(human) (76). Priming and expansion of NKT cells in humans and mice is most potently
induced when their conserved ligand, α-galactosylceramide, is presented to them in the
context of DC (77,78). In the NKT-DC interaction, IL-12 production by the DC is
required for NKT cell activation. Administration of α-galactosylceramide in mice is
associated with acquisition of antigen-specific cytotoxic activity by CD8 T cells, as well
as induction of activation marker CD69 on CD4 T cells. The importance of NKT cells is
demonstrated in NKT deficient mice administered α-galactosylceramide, in which T cell
activation does not occur (79).
Indirect Tolerance Induction by DC
DC activation of NKT cells can result in the secretion of tolerogenic cytokines such as
IL-4 and IL-10. Using the model of anterior chamber associated immune deviated
(ACAID), Faunce et al demonstrated a DC-like population is found in the spleen after
intraocular immunization. These cells secrete a chemokine, MIP-2, which is responsible
for the chemoattraction of NKT cells which induce systemic T cell tolerance to the
immunized antigen (80). This tolerance can be abrogated by administration of antibodies
to IL-10 (81).
As mentioned above, DC can aquire tolerogenic properties after exposure to UVB. The
possibility of tolerogenic DC (ie DC which possess low levels of costimulatory
molecules) activating NKT cells to secrete Th2 cytokines is implied from in vivo studies
showing activation of NKT cells in absence of costimulation leads to secretion of IL-4
and suppressed IFNγ (82). Moodycliffe et al demonstrated the transfer of UVB-induced
antigen-specific immune suppression by NKT cells. These cells act as regulatory cells
suppressing activation of CD4 and CD8 T cells (83).
In the non-obese diabetic mouse (NOD) and diabetic patients there is a defect in DC
differentiation (84, 85). It will be interesting to determine whether this is in part
responsible for the reduced NKT cell activity in NOD mice (86, 87).
Therapeutic Applications of DC-Induced T cell Activation
The ability of DC to act as “natural adjuvants” (88), has stimulated an intense interesting
their utilization for inducing immune responses against poorly immunogenic antigens,
such as those found on tumors and HIV. The first DC clinical trial was aimed at inducing
immunity toward the idiotypic antigen (ID) found on B cell lymphomas. ID is the
specific antibody recombination which is found on all of the B lymphoma cells but is
patient-specific. Immunization of 4 patients with antigen-pulsed (ID and a control
antigen, KLH) monocyte-derived DC induced cell mediated but not antibody response to
ID in all patients. All patients produced antibody and cell mediated response to KLH. Of
the four patients, at 21 month follow-up, one had no evidence of disease, one had
complete remission, and another had partial remission. Administration of DC was well
Although clinical trials with Ag-pulsed DC are in progress for melanoma, prostate cancer
and renal cell carcinoma, results to date have been less than optimal with average
responses occurring in 20-30% of patients (90). This may be due to T cell abnormalities
in cancer patients (91), the production of DC inhibitory factors by the tumor (92), or the
ability of the tumor to induce direct killing of DC (93). When murine DC transfected
with the anti-apoptotic gene Bcl-xl were injected into mice bearing established prostate
cancer, immunologically mediated regression of tumors was observed (94).
A clinical trial using HIV DC pulsed with gag and pol immunogenic peptides was
performed in six HIV patients. Although a cellular and antibody responses to the
peptides were present, no reduction in viral load was seen (95). Expansion of DC using
Flt-3L prior and to, and concominant with HIV-peptide pulse DC vaccine has yielded
stronger antiviral immunity in mice than injection without expansion (96). Clinical trials
using this approach have not been performed.
A caveat in all dendritic cell immunotherapy studies is the origin of the DC. Most
clinical studies utilize monocyte-derived DC grown in the presence of GM-CSF and IL-4
due to the ease of collecting peripheral blood CD14+ cell. DC generated in this manner
have recently been questioned as an ideal immune stimulator due to their defective
migration and NK cell activation abilities, thus generation of DC from other sources may
lead to more profound clinical result (97).
Therapeutic Applications of DC-Induced Tolerance
Clinical trials using DC to induce tolerance have not been conducted. Animal studies
suggest that this approach may be useful. One method of increasing the ability of DC to
induce tolerance is abrogation of their T cell costimulatory capacity. CTLA-4 binds with
high affinity to CD80 and CD86, blocking their interaction with the immunostimulatory
molecule, CD28, on the T cell (17). By treating donor-derived DC with the CTLA-4-Ig,
it is possible to enhance skin graft survival in a rat model of allotransplantation, as well
as to antigen-specifically inhibit T cell proliferation to the alloantigens (98). Using a
similar approach, transfection of CTLA-4-Ig into donor DC can induce acceptance of
BALB/c islet allografts into C57/B6 recipients (99). In these studies the donor-derived
DC were lacking co-stimulatory molecules, however, intragraft DC were not transfected.
The concept of dominant tolerance, perhaps by treated DC inducing T cell anergy must
be addressed in the future. While co-stimulatory molecule expression is needed for
activation of T effector cells it is also required for generation of T regulatory cells.
Blocking the CD80/CD86 interaction with CD28 by administration of CTLA-4-Ig in
NOD mice accelerates disease and leads to a fall in circulating CD4+ CD25+ T regulatory cells (100). Therefore, co-stimulation blockade is an immunomodulatory techniquewhich needs to be more fully understood before clinical application.
Oral tolerance is witnessed by systemic alteration to antigen-specific immune response
after ingestion of the antigen, in part by activation of TGF-β-secreting Th3 cells (101).
Although induction of oral tolerance against self antigens possesses some efficacy in
animal models of autoimmunity, in the clinic this approach has yielded limited results.
An explanation for this may be the high amount of antigen which needs to be ingested to
cause systemic immunomodulation (102). DC are believed to be, at least in part,
responsible for initiating the immunological changes which occur during feeding of
antigen (103). With the idea of augmenting the effect of oral tolerance by in vivo
expansion of DC, Viney et al administered Flt-3L to mice before feeding of the antigen.
This approach reduced the amount of fed antigen needed for induction of oral tolerance
(104). Besides the obvious clinical relevance of these studies, it will be interesting to
determine the characteristics of gut-derived DC which enable them to induce tolerance.
These studies are needed because in some circumstances, feeding of autoantigen can
trigger autoimmunity (105).
Transfection of DC with immunosuppressive molecules may also render them
tolerogenic. IL-10 has been associated with suppression of delayed type hypersensitivity
and induction of tolerance in several systems (106). Donor-derived myeloid DC
transfected with the IL-10 gene allows prolonged survival of renal allografts. The
tolerogenic effects of these DC can be further augmented by transfection of the DC with
TGF-β (107). In contrast, administration of donor-derived immature DC transfected with
the IL-10 gene cause accelerated rejection of cardiac allografts (108). Therefore, the
utility of IL-10-transfected DC as tolerance-inducing cells needs further investigation.
DC have the potential to activate and tolerize T cells depending on lineage (lymphoid or
myeloid), stage of differentiation, expression of surface antigens, and prior manipulation.
Although the study of DC is relatively new, understanding of the biology of these cells
has already provided opportunities to induce and suppress immunological responses at an
antigen-specific level. The clinical utility of DC appears promising in areas such as
cancer immunotherapy, while tolerance-induction therapy is awaiting entrance into the
1. Croft M, Bradley LM, Swain SL. Naive versus memory CD4 T cell response to
antigen. Memory cells are less dependent on accessory cell costimulation and can
respond to many antigen-presenting cell types including resting B cells. J Immunol. 1994
2. Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature. 1998
3. Brocker T, Riedinger M, Karjalainen K. Targeted expression of major
histocompatibility complex (MHC) class II molecules demonstrates that dendritic cells
can induce negative but not positive selection of thymocytes in vivo. J Exp Med. 1997
4. Reid, C. D. L., A. Stackpole, A. Meager, J. Tikepae. 1992. Interaction of tumor
necrosis factor with granulocyte-macrophage colony-stimulating factor and other
cytokines in the regulation of dendritic cell growth in vitro from early bipotent CD34+
progenitors in human bone marrow. J. Immunol. 149:2681.
5. Randolph GJ, Beaulieu S, Lebecque S, Steinman RM, Muller WA. Differentiation of
monocytes into dendritic cells in a model of transendothelial trafficking. Science. 1998
5a. Ferrero E, Bondanza A, Leone BE, Manici S, Poggi A, Zocchi MR. CD14+ CD34+
peripheral blood mononuclear cells migrate across endothelium and give rise to
immunostimulatory dendritic cells. J Immunol. 1998 Mar 15;160(6):2675-83.
6. Ardavin C, Wu L, Li CL, Shortman K. Thymic dendritic cells and T cells develop
simultaneously in the thymus from a common precursor population. Nature. 1993 Apr
7. Shortman K, Caux C. Dendritic cell development: multiple pathways to nature’s
adjuvants. Stem Cells. 1997;15(6):409-19.
8. McLellan AD, Kampgen E. Functions of myeloid and lymphoid dendritic cells.
Immunol Lett. 2000 May 1;72(2):101-5.
9. Merad M, Fong L, Bogenberger J, Engleman EG. Differentiation of myeloid dendritic
cells into CD8alpha-positive dendritic cells in vivo. Blood. 2000 Sep 1;96(5):1865-72.
10.Traver D, Akashi K, Manz M, Merad M, Miyamoto T, Engleman EG, Weissman IL.
Development of CD8alpha-positive dendritic cells from a common myeloid progenitor
Science. 2000 Dec 15;290(5499):2152-4.
11. Faratian D, Colvin L, O’Connell PJ, Morelli AE, Thomson A. Dendritic Cell
Heterogeneity: A Complex Picture Emerges. Graft. 2000; 3(2):54-58
12. Powell JD, Ragheb JA, Kitagawa-Sakakida S, Schwartz RH. Molecular regulation of
interleukin-2 expression by CD28 co-stimulation and anergy. Immunol Rev. 1998
13. Balomenos D, Martinez-A C. Cell-cycle regulation in immunity, tolerance and
autoimmunity. Immunol Today. 2000 Nov;21(11):551-5.
14. Bodor J, Bodorova J, Gress RE. Suppression of T cell function: a potential role for
transcriptional repressor ICER. J Leukoc Biol. 2000 Jun;67(6):774-9
15. Long EO. Regulation of immune responses through inhibitory receptors. Annu Rev
16. Essery G, Feldmann M, Lamb JR. Interleukin-2 can prevent and reverse antigeninduced
unresponsiveness in cloned human T lymphocytes. Immunology. 1988
17. Carreno BM, Bennett F, Chau TA, Ling V, Luxenberg D, Jussif J, Baroja ML,
Madrenas J. CTLA-4 (CD152) can inhibit T cell activation by two different mechanisms
depending on its level of cell surface expression. J Immunol. 2000 Aug 1;165(3):1352-6.
18. Min WP, Gorczynski R, Huang XY, Kushida M, Kim P, Obataki M, Lei J, Suri RM,
Cattral MS. Dendritic cells genetically engineered to express Fas ligand induce donorspecific
hyporesponsiveness and prolong allograft survival. J Immunol. 2000 Jan
19. Jiang SP, Vacchio MS. Multiple mechanisms of peripheral T cell tolerance to the
fetal "allograft". J Immunol. 1998 Apr 1;160(7):3086-90.
20. Hutloff A, Dittrich AM, Beier KC, Eljaschewitsch B, Kraft R, Anagnostopoulos I,
Kroczek RA. ICOS is an inducible T-cell co-stimulator structurally and functionally
related to CD28. Nature. 1999 Jan 21;397(6716):263-6.
21. Walunas TL, Lenschow DJ, Bakker CY, Linsley PS, Freeman GJ, Green JM,
Thompson CB, Bluestone JA. CTLA-4 can function as a negative regulator of T cell
activation. Immunity. 1994 Aug;1(5):405-13.
22. Kurts C, Carbone FR, Krummel MF, Koch KM, Miller JF, Heath WR. Signalling
through CD30 protects against autoimmune diabetes mediated by CD8 T cells.
Nature. 1999 Mar 25;398(6725):341-4.
23. Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, Fitz LJ,
Malenkovich N, Okazaki T, Byrne MC, Horton HF, Fouser L, Carter L, Ling V, Bowman
MR, Carreno BM, Collins M, Wood CR, Honjo T. Engagement of the PD-1
immunoinhibitory receptor by a novel B7 family member leads to negative regulation of
lymphocyte activation. J Exp Med. 2000 Oct 2;192(7):1027-34.
24. Krammer PH. CD95’s deadly mission in the immune system. Nature. 2000 Oct
25. Jeremias I, Herr I, Boehler T, Debatin KM. TRAIL/Apo-2-ligand-induced apoptosis
in human T cells. Eur J Immunol. 1998 Jan;28(1):143-52.
26. Gallucci S, Matzinger P. Danger signals: SOS to the immune system. Curr Opin
Immunol. 2001 Feb;13(1):114-9.
27. Singh B, CLIP IMMUNOMODULATORY PEPTIDE. Canadian Patent Application
# 2205680, filed May 16, 1997.
28. Albert ML, Sauter B, Bhardwaj N. Dendritic cells acquire antigen from apoptotic
cells and induce class I-restricted CTLs. Nature. 1998 Mar 5;392(6671):86-9.
29. Seliger B, Maeurer MJ, Ferrone S. Antigen-processing machinery breakdown and
tumor growth. Immunol Today. 2000 Sep;21(9):455-64.
30. Subklewe M, Paludan C, Tsang M, Mahnke K, Steinman R, Munz C. Dendritic cells
cross-present latency gene products from epstein-barr virus-transformed b cells and
expand tumor-reactive cd8(+) killer t cells. J Exp Med. 2001 Feb 5;193(3):405-12.
31. Jenne L, Arrighi JF, Jonuleit H, Saurat JH, Hauser C. Dendritic cells containing
apoptotic melanoma cells prime human CD8+ T cells for efficient tumor cell lysis.
Cancer Res. 2000 Aug 15;60(16):4446-52.
32. Turley SJ, Inaba K, Garrett WS, Ebersold M, Unternaehrer J, Steinman RM, Mellman
I. Transport of peptide-MHC class II complexes in developing dendritic cells. Science.
2000 Apr 21;288(5465):522-7.
33. Monks CR, Freiberg BA, Kupfer H, Sciaky N, Kupfer A. Three-dimensional
segregation of supramolecular activation clusters in T cells. Nature. 1998 Sep
34. Tamada K, Shimozaki K, Chapoval AI, Zhai Y, Su J, Chen SF, Hsieh SL, Nagata S,
Ni J, Chen L. LIGHT, a TNF-like molecule, costimulates T cell proliferation and is
required for dendritic cell-mediated allogeneic T cell response. J Immunol. 2000 Apr
35. Gramaglia I, Cooper D, Miner KT, Kwon BS, Croft M. Co-stimulation of antigenspecific
CD4 T cells by 4-1BB ligand. Eur J Immunol. 2000 Feb;30(2):392-402.
36. Melero I, Shuford WW, Newby SA, Aruffo A, Ledbetter JA, Hellstrom KE, Mittler
RS, Chen L. Monoclonal antibodies against the 4-1BB T-cell activation molecule
eradicate established tumors. Nat Med. 1997 Jun;3(6):682-5.
37. Chen AI, McAdam AJ, Buhlmann JE, Scott S, Lupher ML Jr, Greenfield EA, Baum
PR, Fanslow WC, Calderhead DM, Freeman GJ, Sharpe AH. Ox40-ligand has a critical
costimulatory role in dendritic cell:T cell interactions. Immunity. 1999 Dec;11(6):689-98.
38. Akiba H, Oshima H, Takeda K, Atsuta M, Nakano H, Nakajima A, Nohara C, Yagita
H, Okumura K. CD28-independent costimulation of T cells by OX40 ligand and CD70
on activated B cells. J Immunol. 1999 Jun 15;162(12):7058-66.
39. Khoury SJ, Gallon L, Chen W, Betres K, Russell ME, Hancock WW, Carpenter CB,
Sayegh MH, Weiner HL. Mechanisms of acquired thymic tolerance in experimental
autoimmune encephalomyelitis: thymic dendritic-enriched cells induce specific
peripheral T cell unresponsiveness in vivo. J Exp Med. 1995 Aug 1;182(2):357-66.
40. Rastellini C, Lu L, Ricordi C, Starzl TE, Rao AS, Thomson AW.
Granulocyte/macrophage colony-stimulating factor-stimulated hepatic dendritic cell
progenitors prolong pancreatic islet allograftsurvival. Transplantation. 1995 Dec
41. Thomson AW, Lu L, Murase N, Demetris AJ, Rao AS, Starzl TE. Microchimerism,
dendritic cell progenitors and transplantation tolerance. Stem Cells. 1995 Nov;13(6):622-
42. Khanna A, Morelli AE, Zhong C, Takayama T, Lu L, Thomson AW. Effects of liverderived
dendritic cell progenitors on Th1- and Th2-like cytokine responses in vitro and in
vivo. J Immunol. 2000 Feb 1;164(3):1346-54.
43. Steptoe RJ, Fu F, Li W, Drakes ML, Lu L, Demetris AJ, Qian S, McKenna HJ,
Thomson AW. Augmentation of dendritic cells in murine organ donors by Flt3 ligand
alters the balance between transplant tolerance and immunity. J Immunol. 1997 Dec
44. Kono DH, Theofilopoulos AN. Genetics of systemic autoimmunity in mouse models
of lupus. Int Rev Immunol. 2000;19(4-5):367-87.
45. Suss G, Shortman K. A subclass of dendritic cells kills CD4 T cells via Fas/Fasligand-
induced apoptosis. J Exp Med. 1996 Apr 1;183(4):1789-96.
46. Kronin V, Winkel K, Suss G, Kelso A, Heath W, Kirberg J, von Boehmer H,
Shortman K. A subclass of dendritic cells regulates the response of naive CD8 T cells by
limiting their IL-2 production. J Immunol. 1996 Nov 1;157(9):3819-27.
47. Barclay, A. N.. 1981. Different reticular elements in rat lymphoid tissue identified by
localization of Ia, Thy-1 and MRC OX-2 antigens. Immunology 44:727
48. Gorczynski, R. M., Z. Chen, X. M. Fu, H. Zeng. 1998. Increased expression of the
novel molecule Ox-2 is involved in prolongation of murine renal allograft survival.
49. Gorczynski RM, Yu K, Clark D. Receptor engagement on cells expressing a ligand
for the tolerance-inducing molecule OX2 induces an immunoregulatory population that
inhibits alloreactivity in vitro and in vivo. J Immunol. 2000 Nov 1;165(9):4854-60.
50. Hoek RM, Ruuls SR, Murphy CA, Wright GJ, Goddard R, Zurawski SM, Blom B,
Homola ME, Streit WJ, Brown MH, Barclay AN, Sedgwick JD. Down-regulation of the
macrophage lineage through interaction with OX2 (CD200). Science. 2000 Dec
51. Young MR, Young ME, Wright MA. Stimulation of immune-suppressive bone
marrow cells by colony-stimulating factors. Exp Hematol. 1990 Aug;18(7):806-11.
52. Young MR, Lozano Y, Coogan M, Wright MA, Young ME, Bagash JM. Stimulation
of the metastatic properties of Lewis-lung-carcinoma cells by autologous granulocytemacrophage
colony-stimulating factor. Int J Cancer. 1992 Feb 20;50(4):628-34.
53. Young MR, Wright MA, Young ME. Antibodies to colony-stimulating factors block
Lewis lung carcinoma cell stimulation of immune-suppressive bone marrow cells. Cancer
Immunol Immunother. 1991;33(3):146-52.
53a. Young MR, Wright MA, Matthews JP, Malik I, Prechel M. Suppression of T cell
proliferation by tumor-induced granulocyte-macrophage progenitor cells producing
transforming growth factor-beta and nitric oxide. J Immunol. 1996 Mar 1;156(5):1916-
54. Lutz MB, Suri RM, Niimi M, Ogilvie AL, Kukutsch NA, Rossner S, Schuler G,
Austyn JM. Immature dendritic cells generated with low doses of GM-CSF in the
absence of IL-4 are maturation resistant and prolong allograft survival in vivo. Eur J
Immunol. 2000 Jul;30(7):1813-22.
55. Bronte V, Chappell DB, Apolloni E, Cabrelle A, Wang M, Hwu P, Restifo NP.
Unopposed production of granulocyte-macrophage colony-stimulating factor by tumors
inhibits CD8+ T cell responses by dysregulating antigen-presenting cell maturation. J
Immunol. 1999 May 15;162(10):5728-37.
56. Almand B, Clark JI, Nikitina E, van Beynen J, English NR, Knight SC, Carbone DP,
Gabrilovich DI. Increased production of immature myeloid cells in cancer patients: a
mechanism of immunosuppression in cancer. J Immunol. 2001 Jan 1;166(1):678-89.
57. Almand B, Resser JR, Lindman B, Nadaf S, Clark JI, Kwon ED, Carbone DP,
Gabrilovich DI. Clinical significance of defective dendritic cell differentiation in cancer.
Clin Cancer Res. 2000 May;6(5):1755-66.
58. Gabrilovich DI, Ishida T, Nadaf S, Ohm JE, Carbone DP. Antibodies to vascular
endothelial growth factor enhance the efficacy of cancer immunotherapy by improving
endogenous dendritic cell function. Clin Cancer Res. 1999 Oct;5(10):2963-70.
59. Meunier L. Ultraviolet light and dendritic cells. Eur J Dermatol. 1999 Jun;9(4):269-
60. Simon JC, Cruz PD Jr, Bergstresser PR, Tigelaar RE. Low dose ultraviolet Birradiated
Langerhans cells preferentially activate CD4+ cells of the T helper 2 subset. J
Immunol. 1990 Oct 1;145(7):2087-91.
61. Schwarz A, Grabbe S, Grosse-Heitmeyer K, Roters B, Riemann H, Luger TA,
Trinchieri G, Schwarz T. Ultraviolet light-induced immune tolerance is mediated via the
Fas/Fas-ligand system. J Immunol. 1998 May 1;160(9):4262-70.
62. Schmitt DA, Ullrich SE. Exposure to ultraviolet radiation causes dendritic
cells/macrophages to secrete immune-suppressive IL-12p40 homodimers. J Immunol.
2000 Sep 15;165(6):3162-7.
63. Kalinski P, Hilkens CM, Snijders A, Snijdewint FG, Kapsenberg ML. IL-12-deficient
dendritic cells, generated in the presence of prostaglandin E2, promote type 2 cytokine
production in maturing human naive T helper cells. J Immunol. 1997 Jul 1;159(1):28-35.
64. Gruner S, Oesterwitz H, Stoppe H, Henke W, Eckert R, Sonnichsen N. Cis-urocanic
acid as a mediator of ultraviolet-light-induced immunosuppression. Semin Hematol. 1992
65. Noonan FP, De Fabo EC. Immunosuppression by ultraviolet B radiation: initiation by
urocanic acid. Immunol Today. 1992 Jul;13(7):250-4.
66. el-Ghorr AA, Norval M. A monoclonal antibody to cis-urocanic acid prevents the
ultraviolet-induced changes in Langerhans cells and delayed hypersensitivity responses in
mice, although not preventing dendritic cell accumulation in lymph nodes draining the
site of irradiation and contact hypersensitivity responses. J Invest Dermatol. 1995
67. Munn DH, Zhou M, Attwood JT, Bondarev I, Conway SJ, Marshall B, Brown C,
Mellor AL. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science.
1998 Aug 21;281(5380):1191-3.
68. Hwu P, Du MX, Lapointe R, Do M, Taylor MW, Young HA. Indoleamine 2,3-
dioxygenase production by human dendritic cells results in the inhibition of T cell
proliferation. J Immunol. 2000 Apr 1;164(7):3596-9.
69. Grohmann U, Fallarino F, Silla S, Bianchi R, Belladonna ML, Vacca C, Micheletti A,
Fioretti MC, Puccetti P. CD40 ligation ablates the tolerogenic potential of lymphoid
dendritic cells. J Immunol. 2001 Jan 1;166(1):277-83.
70. Miller JS, Oelkers S, Verfaillie C, McGlave P. Role of monocytes in the expansion of
human activated natural killer cells. Blood. 1992 Nov 1;80(9):2221-9.
71. Fernandez NC, Lozier A, Flament C, Ricciardi-Castagnoli P, Bellet D, Suter M,
Perricaudet M, Tursz T, Maraskovsky E, Zitvogel L. Dendritic cells directly trigger NK
cell functions: cross-talk relevant in innate anti-tumor immune responses in vivo. Nat
Med. 1999 Apr;5(4):405-11.
72. Yu Y, Hagihara M, Ando K, Gansuvd B, Matsuzawa H, Tsuchiya T, Ueda Y, Inoue
H, Hotta T, Kato S. Enhancement of human cord blood cd34(+) cell-derived NK cell
cytotoxicity by dendritic cells. J Immunol. 2001 Feb 1;166(3):1590-600.
73. Martin-Fontecha A, Assarsson E, Carbone E, Karre K, Ljunggren HG. Triggering of
murine NK cells by CD40 and CD86 (B7-2). J Immunol. 1999 May 15;162(10):5910-6.
74. Wilson JL, Charo J, Martin-Fontecha A, Dellabona P, Casorati G, Chambers BJ,
Kiessling R, Bejarano MT, Ljunggren HG. NK cell triggering by the human
costimulatory molecules CD80 and CD86. J Immunol. 1999 Oct 15;163(8):4207-12.
75. Trinchieri G. Natural killer cells wear different hats: effector cells of innate resistance
and regulatory cells of adaptive immunity and of hematopoiesis. Semin Immunol. 1995
76. Godfrey DI, Hammond KJ, Poulton LD, Smyth MJ, Baxter AG. NKT cells: facts,
functions and fallacies. Immunol Today. 2000 Nov;21(11):573-83.
77. van der Vliet HJ, Nishi N, Koezuka Y, von Blomberg BM, van den Eertwegh AJ,
Porcelli SA, Pinedo HM, Scheper RJ, Giaccone G. Potent expansion of human natural
killer T cells using alpha-galactosylceramide (KRN7000)-loaded monocyte-derived
dendritic cells, cultured in the presence of IL-7 and IL-15. J Immunol Methods. 2001 Jan
78. Kitamura H, Iwakabe K, Yahata T, Nishimura S, Ohta A, Ohmi Y, Sato M, Takeda
K, Okumura K, Van Kaer L, Kawano T, Taniguchi M, The natural killer T (NKT) cell
ligand alpha-galactosylceramide demonstrates its immunopotentiating effect by inducing
interleukin (IL)-12 production by dendritic cells and IL-12 receptor expression on NKT
cells. J Exp Med. 1999 Apr 5;189(7):1121-8.
79. Nishimura T, Kitamura H, Iwakabe K, Yahata T, Ohta A, Sato M, Takeda K,
Okumura K, Van Kaer L, Kawano T, Taniguchi M, Nakui M, Sekimoto M, Koda T. The
interface between innate and acquired immunity: glycolipid antigen presentation by
CD1d-expressing dendritic cells to NKT cells induces the differentiation of antigenspecific
cytotoxic T lymphocytes. Int Immunol. 2000 Jul;12(7):987-94.
80. Faunce DE, Sonoda KH, Stein-Streilein J. MIP-2 recruits NKT cells to the spleen
during tolerance induction. J Immunol. 2001 Jan 1;166(1):313-21.
81. Sonoda KH, Faunce DE, Taniguchi M, Exley M, Balk S, Stein-Streilein J. NK T cellderived
IL-10 is essential for the differentiation of antigen-specific T regulatory cells in
systemic tolerance. J Immunol. 2001 Jan 1;166(1):42-50.
82. Pal E, Tabira T, Kawano T, Taniguchi M, Miyake S, Yamamura T. Costimulationdependent
modulation of experimental autoimmune encephalomyelitis by ligand
stimulation of V alpha 14 NK T cells. J Immunol. 2001 Jan 1;166(1):662-8.
83. Moodycliffe AM, Nghiem D, Clydesdale G, Ullrich SE. Immune suppression and
skin cancer development: regulation by NKT cells. Nat Immunol. 2000 Dec;1(6):521-5.
84. Strid J, Lopes L, Marcinkiewicz J, Petrovska L, Nowak B, Chain BM, Lund T. A
defect in bone marrow derived dendritic cell maturation in the nonobesediabetic mouse.
Clin Exp Immunol. 2001 Mar;123(3):375-381.
85. Takahashi K, Honeyman MC, Harrison LC. Impaired yield, phenotype, and function
of monocyte-derived dendritic cells in humans at risk for insulin-dependent diabetes. J
Immunol. 1998 Sep 1;161(5):2629-35.
86. Hammond KJ, Poulton LD, Palmisano LJ, Silveira PA, Godfrey DI, Baxter AG.
alpha/beta-T cell receptor (TCR)+CD4-CD8- (NKT) thymocytes prevent insulindependent
diabetes mellitus in nonobese diabetic (NOD)/Lt mice by the influence of
interleukin (IL)-4 and/or IL-10. J Exp Med. 1998 Apr 6;187(7):1047-56.
87. Falcone M, Yeung B, Tucker L, Rodriguez E, Sarvetnick N. A defect in interleukin
12-induced activation and interferon gamma secretion of peripheral natural killer T cells
in nonobese diabetic mice suggests new pathogenic mechanisms for insulin-dependent
diabetes mellitus. J Exp Med. 1999 Oct 4;190(7):963-72.
88. Citterio S, Rescigno M, Foti M, Granucci F, Aggujaro D, Gasperi C, Matyszak MK,
Girolomoni G, Ricciardi-Castagnoli P. Dendritic cells as natural adjuvants. Methods.
89. Hsu FJ, Benike C, Fagnoni F, Liles TM, Czerwinski D, Taidi B, Engleman EG, Levy
R. Vaccination of patients with B-cell lymphoma using autologous antigen-pulsed
dendritic cells. Nat Med. 1996 Jan;2(1):52-8.
90. Schadendorf D, Nestle FO. Autologous dendritic cells for treatment of advanced
cancer--an update. Recent Results Cancer Res. 2001;158:236-48.
91. Whiteside TL. Signaling defects in T lymphocytes of patients with malignancy.
Cancer Immunol Immunother. 1999 Oct;48(7):346-52.
92. Menetrier-Caux C, Montmain G, Dieu MC, Bain C, Favrot MC, Caux C, Blay JY.
Inhibition of the differentiation of dendritic cells from CD34 progenitors by tumor
cells: role of interleukin-6 and macrophage colony-stimulating factor. Blood. 1998 Dec
93. Esche C, Shurin GV, Kirkwood JM, Wang GQ, Rabinowich H, Pirtskhalaishvili G,
Shurin MR. Tumor necrosis factor-alpha-promoted expression of Bcl-2 and inhibition of
mitochondrial cytochrome c release mediate resistance of mature dendritic cells to
melanoma-induced apoptosis. Clin Cancer Res. 2001 Mar;7(3 Suppl):974s-979s.
94. Pirtskhalaishvili G, Shurin GV, Gambotto A, Esche C, Wahl M, Yurkovetsky ZR,
Robbins PD, Shurin MR. Transduction of dendritic cells with Bcl-xL increases their
resistance to prostate cancer-induced apoptosis and antitumor effect in mice. J Immunol.
2000 Aug 15;165(4):1956-64.
95. Kundu SK, Engleman E, Benike C, Shapero MH, Dupuis M, van Schooten WC, Eibl
M, Merigan TC. A pilot clinical trial of HIV antigen-pulsed allogeneic and autologous
dendritic cell therapy in HIV-infected patients. AIDS Res Hum Retroviruses. 1998 May
96. Pisarev VM, Parajuli P, Mosley RL, Sublet J, Kelsey L, Sarin PS, Zimmerman DH,
Winship MD, Talmadge JE. Flt3 ligand enhances the immunogenicity of a gag-based
HIV-1 vaccine. Int J Immunopharmacol. 2000 Nov;22(11):865-76.
97. Thurnher M, Zelle-Rieser C, Ramoner R, Bartsch G, Holtl L. The disabled dendritic
cell. FASEB J. 2001 Apr;15(6):1054-61.
98. Harada H, Ishikura H, Nakagawa I, Shindou J, Murakami M, Uede T, Koyanagi T,
Yoshiki T. Abortive alloantigen presentation by donor dendritic cells leads to donorspecific
tolerance: a study with a preoperative CTLA4lg inoculation. Urol Res. 2000
99. O’Rourke RW, Kang SM, Lower JA, Feng S, Ascher NL, Baekkeskov S, Stock PG. A
dendritic cell line genetically modified to express CTLA4-IG as a means to prolong islet
allograft survival. Transplantation. 2000 Apr 15;69(7):1440-6.
100. Salomon B, Lenschow DJ, Rhee L, Ashourian N, Singh B, Sharpe A, Bluestone JA.
B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+
immunoregulatory T cells that control autoimmune diabetes. Immunity. 2000
101. Nagler-Anderson C. Tolerance and immunity in the intestinal immune system. Crit
Rev Immunol. 2000;20(2):103-20.
102. Krause I, Blank M, Shoenfeld Y. Immunomodulation of experimental autoimmune
diseases via oral tolerance. Crit Rev Immunol. 2000;20(1):1-16.
103. Alpan O, Rudomen G, Matzinger P. The Role of Dendritic Cells, B Cells, and M
Cells in Gut-Oriented Immune Responses. J Immunol. 2001 Apr 15;166(8):4843-4852.
104. Viney JL, Mowat AM, O’Malley JM, Williamson E, Fanger NA. Expanding
dendritic cells in vivo enhances the induction of oral tolerance. J Immunol. 1998 Jun
105. Blanas E, Heath WR. Oral administration of antigen can lead to the onset of
autoimmune disease. Int Rev Immunol. 1999;18(3):217-28.
106. Moore KW, de Waal Malefyt R, Coffman RL, O’Garra A. Interleukin-10 and the
interleukin-10 receptor. Annu Rev Immunol. 2001;19:683-765.
107. Gorczynski RM, Bransom J, Cattral M, Huang X, Lei J, Xiaorong L, Min WP, Wan
Y, Gauldie J. Synergy in induction of increased renal allograft survival after portal vein
infusion of dendritic cells transduced to express TGFbeta and IL-10, along with
administration of CHO cells expressing the regulatory molecule OX-2. Clin Immunol.
108. Lee WC, Qiani S, Wan Y, Li W, Xing Z, Gauldie J, Fung JJ, Thomson AW, Lu L.
contrasting effects of myeloid dendritic cells transduced with an adenoviral vector
encoding interleukin-10 on organ allograft and tumour rejection. Immunology. 2000