Indian Journal of Experimental Biology

Vol 45, June, 2007, pp 491-504

Review Article

Dendritic cells and antigen trapping technology ⎯ A revolution in

vaccine/immunotherapy strategy
Chiranjib Pal1, Dipyaman Ganguly2, Kausik Paul3 & Srijib Pal4
1
Department of Zoology, Brahmananda Keshab Chandra College, 111/2, B.T. Road, Bonhooghly, Kolkata 700 108, India
2
Graduate School of Biomedical Sciences, University of Texas at Houston, Health Science Centre, Houston, TX, USA
3
Indian Institute of Chemical Biology, Kolkata 700 032, India
4
Sanjiivani Medical Institute, Kolkata700 108, India

Vaccines based on dendritic cells—the immune system’s key responders to foreign invaders— grabbed the spotlight of
this decade. Scientists have devised a dozen different ways to make dendritic cell vaccines. They have linked dendritic cells
with all kinds of antigens, including peptides derived from gene mutations, tumor/pathogen RNA, viral vectors, and with
whole pathogen/tumor lysate. And they are adding cytokines such as granulocyte macrophage colony stimulating factor or
interleukin 4 during dendritic cell growth or maturation or at the site of vaccination to try to boost response. We are still
learning the best way to generate the dendritic cells, load them with the antigen and send them to the right place in the body,
and use of the biological stage of development of dendritic cells that is best suited to stimulate a response. In the present
review attempts have been made to present a comprehensive synopsis of the history, development and ramifications of
evolving knowledge on dendritic cell biology and the prospects for being developed as a rational immunotherapeutic tool.
Further clinical studies are warranted.

Keywords: Cancer, Dendritic cell (DC), Infectious diseases, Immunotherapy, Viral Diseases, Vaccine

Host defense relies on a concerted action of both
antigen (Ag)-nonspecific innate immunity and Ag-
specific adaptive immunity. Immunology has long
been focused on antigens and lymphocytes, but the
mere presence of these two parties do not always lead
to a perfect immune response. A third party, the
dendritic cells (DC) are found to be the key initiator
and modulator of the primary immune response after
the discovery of a novel cell type in peripheral
lymphoid organs of mice by Steinman in 19731.
Evolutionary pressure has led to the development of
adaptive immunity, the key features of which are, (a)
the ability to rearrange genes of the immunoglobin
family, permitting creation of large diversity of Ag-
specific clones and, (b) immunological memory. Yet
this highly sophisticated and potent system needs to
be instructed and regulated by Ag-presenting cells.
Dendritic cells are a fraction of matured and
terminally differentiated antigen presenting cells
found to be generated from different progenitors with
myeloid or lymphoid commitments, with a unique
ability to induce primary immune response. DC
captures and transfer information from the exogenous
_______________
*Telephone: 033-2577 2486 (O),
E-mail: chiranjibpal@yahoo.co.in,
cpcu.immunology@gmail.com
antigens to the cells of adaptive immune system. Apart
from being highly immunogenic, DC have been shown
to play an important role in peripheral tolerance, as
well as for the regulation of the type of T cell mediated
immune responses and for the long lasting
immunological memory. This review for the most part
of it concentrates on the developing strategies of
immunotherapy by using the dendritic cells.
Heterogeneity of dendritic cell subsets
Mice
At least two distinct pathways of DC development
have been identified in mice. Myeloid precursors give
rise to myeloid DC in presence of granulocyte
macrophage colony stimulating factor2,3. CD8α+
lymphoid DC can also arise from lymphoid
precursors4-8. Transfer of a population of purified
lymphoid precursors into irradiated host results
development of DC that express CD8α. Lymphoid
DC are localized in the T cell rich areas of the
periarteriolar lymphatic sheaths (PALS) in spleen and
lymph nodes6, 9-11. In contrast myeloid DC are in the
marginal zone bridging channels of the spleen9-11.
Both subsets express high levels of CD11c, MHC II
and the costimulatory molecules CD86 and CD40.
Lymphoid DC make higher level of IL-12 and less
492 INDIAN J EXP BIOL, JUNE 2007

phagocytic than the myeloid DC9. responses, DC also participate in the presentation of
Human self-antigen during the course of central and
DC heterogeneity in humans is reflected in all the peripheral T cell tolerance induction via various
four parameters of anatomical localization, mechanisms, including activation of T regulatory
progenitors, functional properties and type of immune (Treg) cells, induction of T cell anergy, and TH1/TH2
response induced12-15. polarization. The exact mechanisms involved in the
(a) Anatomical localization⎯ Depending on decision of a DC to become immunogenic or
anatomical localization the DC are classified as the tolerogenic have not been elucidated, however,
skin epidermal langerhans cells (LC), dermal DC upcoming scientific reports suggests that DC function
(interstitial DC), splenic marginal DC, T-zone is dependent on their maturation stage16.
interdigitating cells, germinal-center DC, thymic DC,
liver DC and blood DC. Recruitment and maturation: The phenotypic
(b) Precursor populations⎯ For instance, in nuances
human at least two subsets of DC precursors circulate Newly generated DC precursors migrate,
in the blood, CD14+CD11c+ monocytes and lineage- presumably through blood stream, from the bone
negative LINnegCD11c-IL3Rα+ precursors DC. The marrow to non-lymphoid tissues, where they
LINnegCD11c+ cells may represent a third precursor, eventually become resident cells. Circulating DC
although these cells are more committed because they precursors accumulate rapidly (within an hour) at the
can spontaneously differentiate into DC when put into sites of antigen deposition in response to the
culture. production of chemokines upon local inflammation as
(c) Function⎯ Precursors of DC correlate with the demonstrated in bronchial epithelium after Ag
functional diversity evidenced from in vitro inhalation17-19. CD34+ hematopoietic cell derived
generation of different subtypes of human DC. CD34+ immature DC expresses CCR6, whose ligand, MIP3α,
precursors from umbilical cord blood and adult bone
marrow cultured in presence of GM-CSF and TNF-α
give rise to functional CD1a+CD14+ Langerhans cells.
CD34+Lin-CD10+ lymphoid restricted precursors
isolated from bone marrow and cultured with
cytokines give rise to DC equivalent to murine
lymphoid-derived DC. Blood monocytes in presence
of cytokines GM-CSF and IL-4, for growth and TNF-
α, for maturation give rise to mature DC type 1
(DC1). CD45RAhiCD11cloIL3Rhi plasmacytoid
precursors from blood, tonsil and thymus in presence
of IL-3 give rise to CD11clo mature DC type 2 (DC2)
(Fig. 1). Precursor DC1 cells produce TNF-α and IL-
6, whereas the precursor DC2 cells rapidly produce
IFN-α and IFN-β in response to the appropriate
microbial stimuli. DC1 cells are found to prime T
cells to produce a TH1 response which is associated
with high production of IL-12 in response to the
appropriate stimuli. In contrast DC2 induce the TH2
response.
(d) Outcome of immune response⎯ The final Fig. 1 ⎯ Pathways of human dendritic cell (DC) development.
outcome of immune response refers to the induction These pathways were deduced from the culture studies in different
of tolerance or immunity. Dendritic cells are experimental conditions67-79. Some DC lineages require
professional APC that play a key role in initiating exogenous stimuli for full activation. Other DC lineages probably
remain at a precursor state in an uninfected individual, because
effector T cell responses in secondary lymphoid they require stimulation by microbial products to produce mature
organs. Equally important to the initiation of effector DC. IPC, Interferron producing Cell; pDC, Precursor of DC;
CLA, Cutaneous lymphocyte associated antigen.
 PAL et. al.: DENDRITIC CELL BASED VACCINATION & IMMUOTHERAPY 493

appears to be the most powerful chemokine guiding

their migration20, 21.
Immature DC are very efficient in Ag capture and
can use several pathways ─ (a) macropinocytosis, (b)
receptor-mediated endocytosis via C-type lectin
receptors (mannose receptor, DEC-205) or Fcγ
receptor type I (CD64) and II (CD32), (c)
phagocytosis of particles such as latex bead, apoptotic
and necrotic cell fragments (involving CD36 and
αvβ3 or αvβ5 integrins), viruses, and bacteria
including mycobacteria, as well as intracellular
parasites such as Leishmania major22.
The antigen or pathogen induces the immature DC
to undergo phenotypic and functional changes that
culminate in the complete transition from the Ag-
capturing cell to APC. DC maturation is intimately
linked with their migration from the peripheral tissue
to the draining lymphoid organs, and therefore these
are the two key events in the life span of DC.
Numerous factors induce and regulate DC maturation
(Fig. 2). The maturation process is associated with
several coordinated cellular events such as (a) loss of
endocytic/phagocytic receptors, (b) upregulation of
costimulatory molecules CD40, CD80, CD83, CD86,
(c) shift in lysosomal compartments with
downregulation of CD68 and upregulation of DC-
lysosome associated membrane protein (DC-LAMP),
(d) changes in MHC II compartments and (e) change
in morphology.
Mature DC downregulate CCR6, the receptor for
MIP3α, consequently escape from local gradient of
chemokines, upregulate the chemokine receptor CCR7
and accordingly acquire responsiveness to MIP3β
(ELC, Exodous 3) and 6Ckine [secondary lymphoid
tissue chemokine (SLC), Exodus2]. Consequently,
maturing DC leave the inflamed tissue and enter the
lymph stream, potentially directed by 6 Ckine that is
expressed on lymphatic vessel. Maturing DC entering
the draining lymph node are driven into the paracortical
areas in response to the production of MIP3β and Fig. 2 ⎯ Maturation of DC. The factors inducing progression
6Ckine by cells spread over the T cell zone. from one stage to another and the properties of each
differentiation/maturation stage.

The decision-makers: Activating the T cells to
shape the immune response
The ability to prime naïve T cells constitutes a
unique and critical function of DC both in vitro and in
vivo. Because virtually all signals to T cells begin at
the cell membrane, the efficacy of vaccines and other
immunotherapies can be enhanced by the inclusion of
ligands that bind to these cell membranes. The
enhanced versatility of new vector systems allows the
combinatorial construction of immunotherapies that
contain elements that target several points in the
pathway of T cell activation23.
At the simplest level, T cell activation requires two
494 INDIAN J EXP BIOL, JUNE 2007
signals. Signal 1 is delivered through the T-cell
receptor (TCR) after engagement by a peptide-MHC
complex. Signal 2, the costimulatory signal, was
thought originally to be coming from CD80 (B7-1)
interacting with CD28 on T cell. The costimulatory
molecules/signals so far identified, fall into three
families ─ the B7 family, the tumor-necrosis factor
(TNF) receptor and cytokines. The B7 family
currently comprises six members with defined
costimulatory activity. The founding members CD80
(B7-1) and CD86 (B7-2), bind to the activating
receptor of T cell, CD28, and a counter regulatory
inhibitory receptor, cytotoxic T-lymphocyte antigen 4
(CTLA4). Newer B7 family members, B7-H1/PDL1
and B7-DC/PDL2, have been reported to have both
costimulatory and inhibitory effect. Their inhibitory
activity is probably mediated through the
programmed cell death 1 (PD1) receptor, which
contains an immunoreceptor tyrosine-based inhibitory
motif (ITIM). B7RP-1, which binds to the activating
receptor inducible costimulatory molecule (ICOS),
seems to be particularly important in T cell-B cell
interaction and antibody production. The receptor for
B7H3 has not been identified yet. TNF receptor
families are upregulated on T cell activation,
indicating that the role of this family might be to
amplify responses once T cell activation has occurred.
T cells can also interact with DC via CD40 ligand-
CD40 signaling pathway leading to increased
expression of CD80/CD86 and cytokine release (IL-1,
TNF, Chemokines and IL-12). Engagement of
RANK, a member of TNFR family by its ligand
(RANKL/TRANCE) expressed on activated T cells,
stimulates the secretion of cytokines like IL-1, IL-6
and IL-12 by DC. Finally cytokines such as IL-12 are
very important in determining the direction of T cell
development i.e., TH1 versus TH2-as a consequence of
T cell stimulation. Once these complex interactions
and signaling outcomes are defined, it should be
possible to build multiple costimulatory signals into
vaccines in an appropriate combinatorial fashion.
Prospects of DC based vaccination and
immunotherapy: Experimental successes and
clinical experiences
DC have been chosen as one of the key factors for
vaccine research from late 1980s when it was found
that human T cell shows proliferative responses to
particulate microbial antigens and are supported by cell
populations enriched for dendritic cells24. The
breakthrough came in mid 90’s when Hsu et. al.
successfully vaccinated patients with B-cell lymphoma
using autologous antigen-pulsed dendritic cells25 and in
case of inactivated influenza viruses, when presented
on dendritic cells in vitro, were shown to elicit human
cytolytic CD8+ T cell responses26.
The accessibility of DC in the immune system,
together with its central role in so many disease
processes, makes it highly appropriate for therapeutic
manipulations. Until recently, immunotherapies tested
clinically have been fairly crude, failing to take
advantage of the molecular pathways that regulate
immunity. The elucidation of specific molecules that
induce DC proliferation and maturation has provided
immunologists with an important tool for the
engineered vaccines with enhanced therapeutic
potency. Recent studies have also shed light on the
pathogenic roles of DC in various diseases such as
autoimmunity, allergy, transplantation, infection and
cancer. This review discusses the ways in which
molecular and cell biological insights into immune
regulation are being applied to design strategies for
both quantitative and qualitative improvement of
immunotherapy for diseases.
Engineered dendritic cells: Way to customized
vaccines
The most common target of active immunotherapy
strategies is the enhancement or modulation of the
function of antigen-presenting cells (APC). This
strategy is based on the concept that the quantitative
and qualitative characteristics of a T cell response to
an antigen depend on the signals that the T cells
receive from the APC. DC are the most potent type of
APC and virtually all stages of DC development and
function can be modulated by engineered vaccines.
GM-CSF and other cytokines, such as FLT3 ligand
and IL-4 that are mitogenic or co-mitogenic, induce
an intermediate stage of DC differentiation that is
characterized by the efficient uptake and processing
of antigen27. DC maturation is dependent on binding
of two classes of receptors present on DC, the Toll
like receptor (TLR) and Tumor necrosis factor
receptor (TNFR) families. TLRs are pattern
recognition receptors, which bind common chemical
moieties that are expressed by pathogens and known
as pathogen associated molecular patterns (PAMPs)
such as lipopolysaccharide (LPS) and unmethylated
CpG DNA sequences. DC have been shown to be
responsible for the capacity of CpG
 PAL et. al.: DENDRITIC CELL BASED VACCINATION & IMMUOTHERAPY
oligodeoxynucleotides to act as an adjuvant for
vaccine against Leishmania major in mice28.
The discovery of specific receptors on DC that are
responsible for receptor mediated endocytosis has
enabled the modification of antigens, so that they can
be more efficiently bound to these DC uptake
receptors. Indeed, antigen-GM-CSF fusion protein is
an example of potential DC targeting29 because GM-
CSF not only stimulates DC proliferation, but might
also act to target the antigen to endosomal
compartments by binding to the GM-CSF receptor.
Fusion of antigen and immunoglobin Fc region
enhanced the Fc receptor (FcR)-mediated antigen
uptake by APC. DNA vaccine encoding an E7-HSP70
fusion protein was 30-fold more effective than the
wild type E7 protein in generating T cell response30.
The two best characterized endogenous DC
maturation factors of the TNF family are TNF-α and
CD40 ligand (CD40L). In vivo ligation of CD40
enhances priming against the endogenous tumor
antigen and promotes CD8+ T cell effector function
in SV40 T antigen transgenic mice31.
The ability to culture DC ex vivo has led to
numerous studies using ex vivo antigen loaded DC as
vaccine against tumor and infectious diseases. The
incorporation of GM-CSF, IL-12 or its encoding gene
into recombinant protein, DNA or viral vaccines has
also been shown to significantly enhance
immunization. Even Dendritic cells engineered to
express the FLT3 ligand stimulate type I immune
response, and induce enhanced cytotoxic T and
natural killer cell cytotoxicities and anti-tumor
immunity32.
Human telomerase reverse transcriptase (hTERT)
is the catalytic component of a functional telomerase
complex, which is important in maintaining cell
immortality33. In most normal human adult cells, the
expression of telomerase is very low and/or transient.
In contrast, almost 90% of human tumors express a
relatively high level of telomerase implying the
possibility of using hTERT as a universal candidate
tumor antigen. Human monocyte-derived dendritic
cells (DC) lack telomerase activity. Similar to other
normal somatic cells, DC express the RNA (hTR)
component but not the catalytic component, hTERT.
Telomerase activity could be reconstituted using
either lipid-mediated transfection of the hTERT
plasmid DNA or transfection of an E1, E3-deleted
adenoviral vector containing the hTERT gene.
495
AdhTERT-transfected DC were able to generate CTL
responses and these CTLs primed against hTERT
exhibited killing of telomerase positive but not
telomerase negative tumor lines of diverse tissue
origins. This study revealed the fact that hTERT gene,
particularly as delivered via the recombinant
adenovirus, may be useful as a vaccine to induce
specific T-cell-mediated tumor immunity in cancer
patients34. Use of adenovirus and retrovirus as vector
for the transduction of DC during vaccine engineering
has been favoured in several recent studies.
Immunization of retrovirus-transfected DC induces
specific cytotoxic T lymphocytes for two distinct
malarial peptides presented by Kd molecule35. DC
transfected with an adenovirus vector encoding IL-12
is a potent vaccine for invasive pulmonary
aspergillosis, a fungal infection36. DC are uniquely
able to decode the fungus-associated information and
translate it in qualitatively different T helper (TH)
immune responses, in vitro and in vivo37. DC sense
fungi in a morphotype-specific manner, through the
engagement of distinct recognition receptors
ultimately affecting cytokine production and
costimulation. Adoptive transfer of different types of
DC activates protective and non-protective TH cells as
well as regulatory T cells and affects the outcome of
the infections. DC transfected with fungal RNA also
restore antifungal resistance in hematopoietic
transplantation. Thus, the remarkable functional
plasticity of DC in response to fungi can be exploited
for the deliberate targeting of cells and pathways of
cell-mediated immunity in response to DC based
fungal vaccines37.
Use of DC in vaccination strategies against
infections
Infectious disease is one of the leading causes of
human death. Particularly in the developing world,
malaria, infectious diarrhea, tuberculosis,
leishmaniasis and many more illness are still existing
and contributing to significant suffering as well as
mortality. For a time infectious diseases were thought
to be under control but at present appearance of AIDS
and other infectious diseases including leishmaniasis
is the major threat for our survival. Ahuja et al.
successfully transferred adoptively the auotologous
DC engineered to secrete IL-12 (IL-12 transfected)
and pulsed ex vivo with soluble protozoan parasite L.
donovani antigens (SLDA) in a mouse model.
496 INDIAN J EXP BIOL, JUNE 2007
Following vaccination it protects the mice from
infection as evidenced from parasite load in liver and
spleen and also from cytokine profile38. By current
estimates, leishmaniasis affects people in 88
countries, with 350 million at risk of contracting the
disease and approximately 2 million new cases each
year (www.who.int/emc/diseases/leish/leisdis1.html).
The devastating impact of this disease is exemplified
by the epidemic of visceral leishmaniasis that
occurred in the 1990s in Sudan. Of all the parasitic
diseases, leishmaniasis is considered the most likely
to succumb to vaccination. There are concerns about
whether the same vaccine will work for all
leishmaniasis. New discovery of vaccines against
leishmaniasis still draws the attention of science.
There are concerns about the cost-effective
production of vaccines against visceral leishmaniasis
because the leishmaniasis is the primary threat for the
developing and under developed tropical countries.
The present authors, being the members of Dr.
Bandyopadhyay’s group for the first time, tried to
formulate an anti-leishmanial immunotherapy strategy
that is really useful for poor countries. The
experimental strategy was successfully developed in
murine model. The cheaper DC-based
immunotherapy combined with antimony based
chemotherapy cures established murine visceral
leishmaniasis39. Bone marrow derived DC40
differentiated after treatment with GM-CSF and IL-4
and pulsed with SLDA in the presence of TNF-α
produced significant amounts of IL-12 (276 ± 40
pg/ml vs 76 ± 22 pg/ml by unpulsed DC), and their
administration in infected mice significantly reduced
splenic and hepatic parasite burden (by 96.6 ± 3.5 and
90.9 ± 4.2% respectively, compared with PBS-treated
infected controls (P<0.0005 for each comparison).
This difference in two organs may be attributed to the
DC subtypes and/or CCR7-mediated migration of DC,
which is dependent on the expression of CCL21 and
CCL19 chemokines by stromal cells within the T cell
areas of secondary lymphoid organs41. The parasite
burden in both the organs also decreased significantly
following administration of unpulsed DC (P<0.05).
SLDA-pulsed or unpulsed Mφ reduced parasite
burden in both organs only marginally, and the
differences were not statistically significant. In the
mouse model of visceral leishmaniasis, the optimum
antileishmanial effect by Sb is achieved by a high
dose of Sb (~500 mg/kg body weight), and only a
marginal effect is seen at 50 mg/kg body weight42.
Treatment with Sb (50 mg/kg body weight) alone
reduced parasite burden by 39.6±13.5% (P<0.05) and
51.7 ± 13.3% (P<0.01) in spleen and liver,
respectively. Strikingly, complete clearance of
parasite burden from spleen and liver was achieved
when infected mice received both SLDA-pulsed DC
and Sb but not in all other experimental groups. The
repetitive in vitro stimulation by SLDA-pulsed DC
has confirmed the fact that CD4+IFNγ+ T cells
effectively emerged in higher percentage, when the
splenocytes were taken from L. donovani infected
mice (13.62%) compared to uninfected mice (6.1%).
Accumulation of IFN-γ mRNA has been detected in
lymph node cells of L. donovani infected mice
administrated with SLDA-pulsed DC, but the
expression of IFN-γ mRNA was not further enhanced
when infected mice received combined therapy with
SLDA-pulsed DC plus Sb. Our data on combined
therapy may have the following explanations. Sb may
have potentiated the antileishmanial activity of DC-
based therapy induced IFN-γ by enhancing IFN-γ
signaling. Alternatively, Sb, by its ability to potentiate
the production of reactive oxygen species43 and to
induce programmed cell death in Leishmania, may
provide additional antileishmanial activity over DC-
based therapy induced IFN-γ.
Toxoplasma gondii can cause severe sequelae in
the fetus when the mother acquires the infection
during pregnancy, as well as life-threatening
neuropathy in immunocompromised patients, in
particular those with AIDS. T. gondii antigen-pulsed-
dendritic cell-derived exosomes induce a protective
immune response against T. gondii infection.
Adoptive transfer of T. gondii-pulsed DC-derived
exosomes to the spleen elicited a strong systemic
Th1-modulated Toxoplasma-specific immune
response in vivo, and conferred good protection
against infection. These findings support the
possibility that DC-derived exosomes can be used for
T. gondii immunoprophylaxis and for immuno-
prophylaxis against many other pathogens44.
Burkholderia pseudomallei, the causative agent of
melioidosis, is a gram-negative bacterium which can
cause either chronic infections or acute lethal sepsis in
infected individuals. The disease is endemic in
Southeast Asia and northern Australia. Upon virulent
challenge with B. pseudomallei strains K96243,
NCTC 4845 or 576, animals immunized with
 PAL et. al.: DENDRITIC CELL BASED VACCINATION & IMMUOTHERAPY
dendritic cells that were pulsed with heat-killed
K96243 and matured in the presence of CpG 1826
showed significant levels of protection45.
DC in anti-viral immunotherapy
Control of a viral infection in vivo requires a rapid
and efficient cytotoxic T lymphocyte response.
Lentivirus mediated introduction of antigen in DC
confers a protective antiviral immunity in vivo in a
lymphocytic choriomeningitis virus model. Therefore,
lentiviral vectors may be excellent vaccine candidates
for viral infections46. Induction of protective
immunity to bacteria Listeria monocytogenes was
observed in case of DC retrovirally transfected with a
cytotoxic T lymphocyte epitope minigene47. In a
preliminary investigation on therapeutic DC based
vaccine, 18 chronically HIV-1 infected and untreated
individuals showing stable viral loads at least for 6
months were immunized with autologous monocyte
derived DC loaded with autologous aldrithiol-2-
inactivated HIV-1. Plasma viral load levels were
decreased by 80% (median) over the first 112 day
following immunization. Prolonged suppression of
viral load of more than 90% was seen in 8 individuals
for the last 1 year. The suppression of viral load was
positively correlated with HIV-1 specific IL-2 or IFN-
γ expressing CD4+ T cells and with HIV-1 gag
specific perforin expressing CD8+ effector cells,
suggesting that a robust virus-specific CD4+ T helper
(TH1) response is required for inducing and
maintaining virus specific CD8+ effector to contain
HIV-1 in vivo. The results suggest that inactivated
whole virus pulsed DC vaccines could be a promising
strategy for treating people with chronic HIV-1
infection48.
A majority of hepatitis C virus (HCV)-infected
individuals becomes chronically infected, which
can result in liver cirrhosis and hepatocellular
carcinoma. Patients with chronic HCV are unable to
prime and maintain vigorous T-cell responses.
Hepatitis C virus (HCV) specific T cell responses
have been suggested to play a significant role in
viral clearance. Recombinant adenoviral vectors
containing HCV derived Core and NS3 genes were
used to endogenously express HCV Core and NS3
proteins in human DC. These HCV-antigen
expressing DC were used to prime and stimulate
autologous T cells obtained from uninfected healthy
donors. The DC expressing HCV Core or NS3
497
antigens were able to stimulate T cells to produce
various cytokines and proliferate in HCV Ag-
dependent manner49-52. Relative to mice inoculated
with non-transfected dendritic cells, splenocytes
derived from mice immunized with either hepatitis
C virus Core-transfected or non-structural 5-
transfected dendritic cells showed 3 to 5-fold
greater antigen-specific cytotoxic T lymphocyte
activity. These findings suggest that vaccination
with protein-transfected dendritic cells may
constitute an important antiviral strategy for
hepatitis C virus53.
Immunization with Ad-S-transfected [Recombinant
adenovirus expressing hepatitis B surface antigen
(HBsAg) (Ad-S)] DC effectively induced HBsAg-
specific CTLs in vivo and down-regulated the
circulating HBsAg and HBV DNA in HBV transgenic
mice. Furthermore, these efficacies were stronger than
that of HBsAg-pulsed DC and plasmid DNA. Thus,
DC transfected with recombinant adenovirus may be a
promising candidate for an effective CTL-based
therapeutic vaccine against HBV54. The DC from
chronic hepatitis B patients had a lower expression of
costimulatory molecules CD80, CD86 and impaired
allogeneic mixed lymphocyte reaction capacity
compared to those from normal controls. However,
the impaired DC function could be restored partially
by a cytokine cocktail supplementation in vitro.
Mature DC loaded with HBsAg or HBcAg showed a
greater capacity for autologous T cell proliferation
and antigen-specific IFN-γ production than immature
DC. Moreover, as a DC-loading antigen, HBcAg was
more immunogenic than HBsAg. The impaired
function of DC in patients with CHB may be restored
by supplementation in vitro with a cocktail of
cytokines, and therapeutic DC vaccines might be
effective to treat CHB infection in humans55.
DC in anti-tumor immunotherapy
The supremacy of DC based anti-tumor vaccination
strategies can be judged clearly from a single
injection of CD34+ progenitor-derived dendritic cell
vaccine leading to induction of T-cell immunity in
patients with stage IV melanoma56. Treatment of
malignant glioma is difficult and discouraging. Even
after resection and maximal adjuvant therapy, the
prognosis remains poor. Yu et. al.57 successfully
proved the idea that vaccination of malignant glioma
patients with peptide-pulsed DC elicits systemic
498 INDIAN J EXP BIOL, JUNE 2007
Fig. 3 ⎯ Ways of DC-based vaccination. Immature DC are
efficient in phagocytosis compared to matured DC. Peptide eluted
from cell lysate of tumors or other pathogens like Leishmania sp.,
Toxoplasma sp. are successfully tried for vaccination. RNA/DNA
from bacteria, virus or fungi are good agent for DC pulsed
vaccination. Immature DC engulfs apoptic bodies more efficiently
and proved as best adjuvant against tumor cells. TNF-α, CD40L,
IL-10, IL-6 etc. are used as maturation stimuli to mature the DC
before administration.
cytotoxicity and intracranial T-cell infiltration. The
same group demonstrated that an active
immunotherapy strategy with tumor lysate pulsed
autologous DC could be possible for generating
antigen-specific cytotoxicity in phase I study in brain
tumor patients58. Results of such a phase I study
utilizing monocyte-derived DC pulsed with tumor
RNA in children and young adults with brain cancer
showed that DC-RNA vaccines (Fig. 3) were both
safe and feasible in children with tumors of the central
nervous system with a single leukapheresis59.
Immunoglobin produced by myeloma cells is
clone-specific and carries an idiotype which may be a
suitable tumor-specific antigen for immune targeting.
Advances in DC technology suggest an opportunity
for using this potent antigen presentation system to
deliver myeloma Id to the autologous host to elicit
anti-tumor immune responses. Murine dendritic cells
pulsed with an anti-idiotype antibody induce antigen-
specific protective anti-tumor immunity 60.
Heat-shock protein-based anticancer immuno-
therapy is an idea mooted in early 90’s. But the use of
dendritic cells for this purpose is just new and novel.
Heat-treated CT-26 (HSCT) cells showed a higher
HSP70 protein expression. Pulsing with heat shocked
CT-26 cell lysate elevated the co-stimulatory and
MHC-II molecule expression on bone marrow derived
DC as well as IL-12 p70 secretion. The frequency of
IFN-γ secreting CTLs induced by HSCT-26 DC was
significantly more than that induced by non heat
treated CT-26 lysate pulsed-DC. Heat-shocked tumor
cell lysate-pulsed DC can evoke anti-tumor immune
response in vivo effectively and serve as a novel DC-
based tumor vaccine 61. The mice vaccinated with
HSP105-pulsed BM-DC were markedly protected
from the growth of subcutaneous tumors,
accompanied by a massive infiltration of both CD4+
T cells and CD8+ T cells into the tumors. Both CD4+
T cells and CD8+ T cells play a crucial role in anti-
tumor immunity. In this study both CD4+ T cells and
CD8+ T cells specific to HSP105 were induced by
stimulation with HSP105-pulsed DC. As a result,
vaccination of mice with BM-DC pulsed with
HSP105 could elicit a stronger tumor rejection
compared to DNA vaccination62.
DC fused with tumor cells may also be effective
for immune response induction. A pilot clinical trial
using dendritomas, purified hybrids from the fusion of
dendritic cells and tumor cells combined with a low
dose of IL-2 was conducted in metastatic melanoma
patients in order to determine its safety and potential
immunological and clinical responses. Eight of nine
patients demonstrated immunologic reactions by
increased IFN-γ expressing T cells63.
DC can capture antigen from apoptotic tumor cells
and induce MHC class I and class II restricted
responses. Dendritic cells loaded with apoptotic tumor
cells induce stronger T cell responses than dendritic
cell-tumor hybrids in B-CLL. But endocytosed
apoptotic tumor cells induced a significantly stronger
T cell response than DC hybrids and as such should
be a better candidate for vaccine production64.
Autologous DC transfected with total renal tumor
 PAL et. al.: DENDRITIC CELL BASED VACCINATION & IMMUOTHERAPY
Fig. 4 ⎯ Attempts at antitumor vaccination using the dendritic cells over the past few years80–108. Most successful attempts have been
made in case of neuroblastoma and multiple myeloma.
RNA have been shown to be potent stimulators of
CTLs and anti-tumor immunity in vitro. A Phase I
trial revealed that the tumor-related mortality of the
study subjects was unexpectedly low with only 3 of
10 patients dying from disease after a mean follow-up
of 19.8 months. These data provide a scientific
rationale for continued clinical investigation of this
polyvalent vaccine strategy in the treatment of
metastatic renal cell carcinoma65 and potentially, for
other cancers (Fig. 4).
Provenge®: DC vaccine from bench to bedside
Provenge® is a therapeutic vaccine composed of
autologous antigen presenting cells cultured ex vivo
with a recombinant fusion antigen consisting of
prostatic acid phosphatase (PAP) linked to
granulocyte macrophage colony stimulating factor.
The drug is in the final stage of clinical evaluation in
men with androgen-independent prostate cancer.
Results from a completed phase 3, double-blind
499
placebo controlled trial suggest that in men with
Gleason ≤7 tumors, Provenge® delays disease
progression, delays the onset of disease related pain
and results in a survival advantage when compared to
patients who had been randomized to placebo66.
Epilogue
The quest for the ideal immunotherapeutic
approach has for long been the desired objective in
the treatment of cancer and other infectious diseases
(Table 1). DC used as an adjuvant in the
immunotherapy for patients with malignant glioma
seems to be promising. As with DC vaccination trials
for other malignancies, DC immunotherapy of glioma
proved to be biologically safe and without major side
effects. Nevertheless, its efficacy remains to be more
closely examined in randomized and controlled
clinical trials. The development of advanced methods
for genetic manipulation and transduction of DC prior
to vaccination in humans may considerably increase
500 INDIAN J EXP BIOL, JUNE 2007

Table 1 ⎯ Major attempts at DC based vaccination: Strategy, experiment and success

Attempts taken Source of antigen Strategy Brief result Ref.
Therapeutic against L.donovani antigen IL-12 transfected DC Live parasites were not detected in the 36
experimental visceral (SLDA) liver of mice vaccinated with IL-12-
leishmaniasis transfected, SLDA-pulsed DC.
Therapeutic against L.donovani antigen Bone marrow derived DC Complete clearance of parasitemia from 37
experimental visceral (SLDA) in combination with SAG spleen and liver with Th1 biased
leishmaniasis response.
Prophylactic against T.gondii antigen DC derived exosome Toxoplasma specific Th1 response in 38
T.gondii vivo, good protection against infection.
Therapeutic against Autologous adrithiol- Autologous monocyte Suppression of viral load, generation of 42
patients infected with 2 inactivated HIV-1 derived DC HIV-1 specific IL-2+CD4+, IFN-γ+CD4+
HIV-1 T cells and HIV-1 gag specific perforin+
CD8+ T cells.
Immunization against Recombinant- Bone marrow derived DC HBsAg-Ad-S transfected DC effectively 48
HBV in transgenic mice HBsAg-Ad-S (BM DC) induced Tc cells and HBsAg-specific
transduced DC CTL in vivo and down-regulated the
circulating HBsAg.
Therapeutic against Surface peptides of Autologous PBMC Development of systemic cytotoxicity in 51,52
malignant glioma patient autologous glioma derived DC four of seven tested patients. Robust
cells intratumoral cytotoxic and memory T-
cell infiltration was detected in two of
four patients.
Immunization syngenic DCs pulsed with heat Bone marrow derived DC HSCT-26 DC elevated the co-stimulatory 55
BALB/c mice shocked colon cancer (BM DC) and MHC-II molecule expression of
(CT-26) cell lysate BMDC as well as IL-12p70 secretion.
(HSCT-26 DC) The IFN-γ secreting CTL induced by
HSCT-26 DC were significantly more
than those induced by CT-26 DC.
Therapeutic against DC-Tumor cell Autologous DC Eight of nine patients demonstrated 57
metastatic melanoma in hybrid immunologic reactions by increased IFN-
patient (Dendritomas) γ expressing T cells.
Therapeutic against renal Renal tumor RNA- Autologous DC In six of seven evaluable subjects, 59
tumor in patient transfected DC expansion of tumor-specific T cells was
detected after immunization.
Provenge® Recombinant Autologous DC Provenge® delays disease progression and 66
Therapeutic vaccine prostatic acid results in a survival advantage when
against prostate cancer phosphatase (PAP) compared to patients who had been
linked to GMCSF randomized to placebo.

the clinical benefits from this type of biological
treatment.
Dendritic cells, being recognized to have the
unique capability of initiating a strong primary
immune response, has long been identified to be an
adept machinery for vaccination against different
nonself pathogenic antigens and modified-self
tumor antigens. Pathogen-specific immunotherapies
or tumor-targeting vaccination strategies can be far
more strengthened by use of a potent natural
adjuvant like dendritic cells. Moreover,
characterization of the tolerogenic properties of few
dendritic cell subsets can open up new avenues in
the form of tolerizing-immunotherapy against
autoimmune disorders or post-transplantation graft
versus host diseases. The investigations in these
new fields are still in a nascent state of
development. Nevertheless, scads of cerebration
have already gone into it and the literature reporting
the myriad stories of success and pitfalls have
enriched the understanding in a great way.
Acknowledgement
Thanks are due to Dr. Santu Bandyopadhyay for
constant inspiration and suggestions and UGC, New
Delhi for financial assistance.
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