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MICROSCOPY RESEARCH AND TECHNIQUE 53:241–245 (2001)

Immunopathogenesis of Delayed-Type Hypersensitivity

KAZUO KOBAYASHI,1* KENJI KANEDA,2 AND TSUYOSHI KASAMA3
1
Department of Host Defense, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
2
Department of Anatomy, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
3
First Department of Internal Medicine, Showa University School of Medicine, Tokyo 142-8666, Japan

KEY WORDS cell-mediated immunity; granulomatous inflammation; protection; intracellular

infection
ABSTRACT Cell-mediated immunity is defined as a beneficial host response characterized by
an expanded population of specific T cells, which, in the presence of antigens, produce cytokines
locally. The activation and recruitment of cells into an area of inflammation is a crucial step in the
development of DTH responses. DTH is immunologically a process similar to cell-mediated immu-
nity, involving T cells and cytokines. CD4 T helper (Th) 1 cells, differentiated from naive Th cells
by IL-12 and IL-18 produced from macrophages, play a regulatory role in the expression of DTH and
activation of macrophages via interferon ␥ generated by Th1 and natural killer cells. Macrophages
accumulate at the site of DTH and become activated through the CD4 Th1 cell-cytokine-macro-
phage axis. However, DTH leads to pathologic responses, such as granulomatous inflammation,
calcification, caseation necrosis, and cavity formation. Granulomas usually form as a result of the
persistence of a nondegradable product or as the result of DTH responses. DTH is also required for
host defense against etiologic agents, such as Mycobacterium tuberculosis. The expression of
cell-mediated immunity/DTH is a double-edged sword that may contribute to both clearance of the
etiologic agent and tissue damage. Microsc. Res. Tech. 53:241–245, 2001. © 2001 Wiley-Liss, Inc.

INTRODUCTION tissue damage by release of lysosomal enzymes and

Humans live in an environment abundant with sub-
stances capable of inducing immunologic responses.
Contact with antigen leads not only to induction of a
protective immune response, but also to reactions that
can damage tissues. Exogenous antigens occur in mi-
crobes, dust, pollens, foods, drugs, chemicals, and blood
products used in clinical practice. The immune re-
sponses that result from exogenous antigens express a
variety of forms, ranging from mild symptoms, such as
itching of the skin, to potentially fatal diseases, such as
anaphylaxis. The various reactions produced are
known as hypersensitivity reactions, and these can be
initiated either by the interaction of antigen with hu-
moral antibody or by cell-mediated immune mecha-
nisms (Cotran et al., 1999; Galli and Lantz, 1999).
Tissue-damaging immune reactions may be evoked
not only by exogenous antigens, but also by those that
are intrinsic to the body (endogenous). Hypersensitiv-
ity diseases can be classified on the basis of the immu-
nologic mechanism that mediates the disease (Table 1)
(Cotran et al., 1999; Galli and Lantz, 1999; Majno and
Joris, 1996).
● In type I disease, the immune response releases va-
soactive and spasmogenic substances that act on ves-
sels and smooth muscle and proinflammatory cyto-
kines that recruit inflammatory cells.
● In type II disorders, humoral antibodies participate
directly in injuring cells by predisposing them to
phagocytosis or lysis.
● Type III disorders are best remembered as immune
complex diseases, in which humoral antibodies bind
antigen and activate complement. The fractions of
complement then attract neutrophils, which produce
generation of toxic free radicals.
● Type IV disorders involve tissue injury in which cell-
mediated immune responses with sensitized T lym-
phocytes are the cause of the cellular and tissue
injury. Cell-mediated immunity contains the classic
delayed-type hypersensitivity (DTH) reaction initi-
ated by CD4 T cells and direct cell cytotoxicity me-
diated by CD8 T cells. It is the principal pattern of
immunologic response not only to a variety of intra-
cellular microbiologic agents, particularly Mycobac-
terium tuberculosis, but also to many viruses, fungi,
protozoa, and parasites. Contact skin sensitivity to
chemical agents and graft rejection are other in-
stances of cell-mediated reactions.
CELLULAR COMPONENTS OF DTH
Granulomas are characterized by the expression of
classical DTH reaction, which is the “nuisance version”
of cell-mediated immunity (Dannenberg and Rook,
1994). A granuloma is a focal area of granulomatous
inflammation that is chronic inflammatory response in
which the predominant cell type is activated macro-
phages with epithelioid appearance. Thus, a granu-
loma is defined as a collection of cells of the monocyte
lineage (macrophages, epithelioid cells, and multinu-
cleated giant cells; fused epithelioid cells) with or with-
*Correspondence to: Kazuo Kobayashi, Department of Host Defense, Osaka
City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku,
Osaka 545-8585, Japan. E-mail: kobayak@med.osaka-cu.ac.jp.
Received 7 September 2000; accepted in revised form 19 September 2000.
Contract grant sponsor: Ministry of Health, Labour and Welfare; Contract
grant sponsor: The United States–Japan Cooperative Medical Science Program
against Tuberculosis and Leprosy; Contract grant sponsor: Ministry of the En-
vironment.

© 2001 WILEY-LISS, INC.

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242 K. KOBAYASHI ET AL.

TABLE 1. Classification of immunologically-mediated adverse/hypersensitivity reactions

Type Key components Examples
I Anaphylactic type IgE, mast cells Hives, pollinosis, bronchial asthma, anaphylaxis, food allergy
II Cytotoxic type IgG, IgM to cell surface antigen, Goodpasture syndrome, bullous pemphigus, erythroblastosis
complement, cytotoxic cells fetalis, autoimmune hemolytic anemia
III Immune complex disease Immune complexes, Arthus reaction, serum sickness, poststreptococcal
complement, glomerulonephritis, systemic lupus erythematosus
polymorphonuclear leukocytes
IV Cell-mediated (delayed) T lymphocytes, macrophages, Granulomatous diseases: tuberculosis and leprosy, contact
hypersensitivity cytokines dermatitis, Mantoux reaction; Direct cell cytotoxicity: graft
rejection and virally infected cells

Fig. 1. The Th1 and Th2 paradigm.

out the additional presence of other inflammatory cells
(Kunkel et al., 1989). Granuloma-inducing agents per-
sist in the tissues because they are insoluble or poorly
degradable (Kasahara et al., 1988; Shikama et al.,
1989). The common histopathologic feature, infiltrating
mononuclear leukocytes, is seen in a variety of granu-
lomatous diseases caused by infectious agents (tuber-
culosis, leprosy, syphilis, cat-scratch disease, histoplas-
mosis, coccidioidomycosis, leishmaniasis, and schisto-
somiasis), non-infectious agents (pneumoconiosis,
silicosis, and berylliosis), or unknown agents (Wegen-
er’s granulomatosis, Crohn’s disease, and sarcoidosis).
The sequence of cellular events in DTH can be exem-
plified by the tuberculin reaction, which begins with
the first exposure of the individual to M. tuberculosis.
Naive CD4 T helper (Th) cells recognize peptides de-
rived from tubercle bacilli in association with class II
molecules on the surface of antigen-presenting cells,
such as monocytes or dendritic cells (Kaufmann, 1995).
This initial encounter derives the differentiation of na-
ive CD4 Th cells to Th1 cells by cytokines, including
interleukin 12 (IL-12) and IL-18 derived from antigen-
presenting cells and interferon ␥ (IFN-␥) produced
from natural killer and Th1 cells (Trinchieri, 1995).
The induction of Th1 cells is of signal importance be-
cause the expression of DTH depends in large part on
cytokines secreted by Th1 cells (Fig. 1).
EFFECTOR MOLECULES OF DTH
Monocytes/macrophages regulate various cellular
functions by virtue of synthesizing unique cytokines
that initiate and control inflammatory and immune
reactions in both local and distantly located cell popu-
lations. Alveolar macrophages represent the first line
of defense in the lung against inhaled environmental
agents, and then they can produce a plethora of cyto-
kines, including chemokines (IL-8, monocyte chemoat-
tractant protein-1 [MCP-1], macrophage inflammatory
protein-1␣ [MIP-1␣]) (Kunkel, 1999), proinflammatory
cytokines (IL-1, IL-6, tumor necrosis factor ␣ [TNF-␣])
(Oppenheim and Neta, 1994), and immunoregulatory
cytokines (IL-10, IL-12) (Trinchieri, 1997). IL-8,
MCP-1, and MIP-1␣ are chemokines that facilitate the
recruitment of inflammatory cells including neutro-
phils, monocytes, and lymphocytes to the site of DTH
reaction. In addition, chemokines activate inflamma-
tory cells infiltrated into the lesion (Oppenheim et al.,
1991). Human blood mononuclear cells preferentially
produced CC chemokines in response to tuberculin and
M. tuberculosis (Kasahara et al., 1998, 1994), which

PATHOGENESIS OF DELAYED-TYPE HYPERSENSITIVITY
Fig. 2. Pathologic and protective outcomes of cell-mediated immu-
nity.
can induce the development of granulomatous inflam-
mation. Chemokines produced during the inflamma-
tory process may determine the extent, quality, and
duration of the cellular infiltrate. CC chemokines acti-
vate and recruit mononuclear cells into the lesion, and
consequently contribute to local accumulation of mono-
nuclear cells (granulomas). In the process, proinflam-
matory cytokines, such as IL-1 and TNF-␣, play an
important role, because they stimulate the production
of chemokines from inflammatory cells including mac-
rophages.
IL-12 has been identified as the most powerful in-
ducer of IFN-␥ production by Th1 and natural killer
(NK) cells and also stimulates the production of gran-
ulocyte-macrophage colony-stimulating factor (GM-
CSF) and TNF-␣ (Trinchieri, 1995). IL-12 induces the
differentiation of Th1 cells from naive Th cells and,
consequently, initiates cell-mediated immunity that
leads to the expression of DTH/granulomatous re-
sponse and plays a protective role in infections with
intracellular pathogens such as mycobacteria (Koba-
yashi et al., 1995, 1996, 1997, 1998) (Fig. 2). This
cytokine represents an important regulatory bridge be-
tween innate resistance and adaptive immunity
(Trinchieri, 1995).
Th1 AND Th2 PARADIGM IN DTH
Differentiated CD4 Th cells can be divided into Th1
and Th2 subsets based on their cytokine production
following antigenic stimulation (Mosmann and Sad,
1996). Th1 cells produce IFN-␥ and mediate DTH and
protection against intracellular pathogens. The Th2
subset produces IL-4, IL-5, IL-10, and IL-13 and is
implicated in humoral and allergic responses (Fig. 1).
The differentiation of these Th subsets is dependent on
cytokine-stimulated genetic programs. IL-12-activated
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243
signal transducer and activator of transcription (Stat)
4 is required for the development of fully functional
Th1 cells. By contrast, IL-4-activated Stat6 is essential
for the differentiation of Th2 cells (Wurster et al.,
2000). Chemokines produced during the inflammatory
process may determine the extent, quality, and dura-
tion of the cellular infiltrate. Th1 cells express CC
chemokine receptor, CCR5 (binds MIP-1␣, MIP-1␤, and
regulated on activation normal T expressed and se-
creted; RANTES), whereas Th2 cells express CCR3
(binds eotaxin-1, eotaxin-2, and MCP-3) (Romagnani et
al., 2000; Rossi and Zlotnik, 2000). The interaction
between chemokines and their receptors may lead to
recruitment and activation of polarized Th cells in the
lesion.
In addition, adhesion molecules may be crucial in
granulomatous inflammation, because recruited mono-
cytes/macrophages are tightly bound in the lesion. In-
deed, intercellular adhesion molecule-1 and its ligand
are detected in the lesion caused by mycobacteria (Sul-
livan et al., 1991), schistosoma (Lukacs et al., 1994),
and foreign bodies (Power et al., 1994). Adhesion mol-
ecules are inducible by stimulation with proinflamma-
tory macrophage-derived cytokines, including IL-1 and
TNF-␣ (Bevilacqua, 1993). Thus, cytokines/chemokines
and adhesion molecules form a complex network of
cellular interactions in DTH/granulomatous inflamma-
tion.
TISSUE DAMAGE BY DTH
DTH is a major mechanism of defense against intra-
cellular pathogens (Kobayashi et al., 1996; Kobayashi
and Yoshida, 1996), including mycobacteria, fungi, and
certain parasites, and may also be involved in trans-
plant rejection and tumor immunity. In addition to its
beneficial, protective role, DTH can also be a cause of
disease, including granulomatous inflammation, calci-
fication, caseation necrosis, and cavity formation (Fig.
2). Expression of cell-mediated immunity, therefore,
results in pathologic and protective outcomes. Addi-
tionally, granulomas develop an encapsulation rim of
fibroblasts and connective tissue. Consequently, the
lesions lead to functional loss of organs, such as chronic
respiratory failure. IL-12 produced by antigen-present-
ing cells, the principal mediator of cell-mediated immu-
nity and DTH, can augment both granulomatous re-
sponse and protection against mycobacterial infection
(Kobayashi et al., 1995, 1996, 1998). IL-12 can stimu-
late production of IFN-␥, TNF-␣, and GM-CSF, which
activate macrophages, NK cells, and naive Th cells into
Th1 cells (Trinchieri, 1997). The IL-12 network partic-
ipates in augmentation of inflammation and protection
from the etiologic agent. Because IL-12 is an initiation
cytokine in the expression of cell-mediated immunity,
in turn, cell-mediated immunity is a double-edged
sword that may contribute to both clearance of infec-
tion and tissue damage (Kobayashi and Yoshida, 1996).
The interaction of inflammatory cells and cytokines
participates in the development of lesions.
SUPPRESSION OF DTH IN
GRANULOMATOUS DISEASE
The expression of cell-mediated immunity and/or
DTH is important in granuloma formation. For in-
stance, granulomatous inflammation at the site of M.

244 K. KOBAYASHI ET AL.
tuberculosis infection occurs coincidentally with the
development of DTH demonstrated by positive skin
reaction to tuberculin after 2 or 3 weeks of the infection
(Dannenberg, 1991). Up to 25% of patients with pul-
monary tuberculosis have a negative tuberculin skin
test (anergy) on initial evaluation (Nash and Douglass,
1980). This percentage is increased in those with dis-
seminated or miliary tuberculosis (Daniel et al., 1981).
Anergy is defined as the absence of an appropriate
DTH reaction and may be either nonspecific, with lack
of T cell responses to many types of antigens, or spe-
cific, with lack of T cell responses to a particular anti-
gen (Kobayashi and Yoshida, 1996). Antigen-nonspe-
cific anergy occurs in patients with granulomatous dis-
eases including tuberculosis (Daniel et al., 1981) and
sarcoidosis (Thomas and Hunninghake, 1987). Using
experimental mouse models, we have demonstrated
that anergy is found in the active stage of granuloma-
tous inflammation (Kobayashi et al., 1985a,b). Anergic
animals show the diminution of both in vivo (footpad
responses) and in vitro (lymphoproliferation and IL-2
production) manifestations of cell-mediated immunity
while active lesions contain a large amount of granu-
lomatogenic cytokines such as IL-1, TNF-␣, and mac-
rophage migration inhibition factor (Kobayashi et al.,
1985a,b). Although the precise mechanism of anergy in
granulomatous disease remains unknown, antigen-
nonspecific anergy may be explained by (1) compart-
mentalization of effector cells in the lesion, (2) loss of
chemotactic gradient by the excess amount of circulat-
ing chemokines, and/or (3) cytokine-dependent down-
regulation (stimulation with the hypothalamus-pitu-
itary-adrenal axis and induction of prostaglandin E,
which are responsible for immunosuppression) (Koba-
yashi et al., 1986, 1990; Kobayashi and Yoshida, 1996).
CONCLUDING REMARKS
Cell-mediated immunity is defined as a beneficial
host response characterized by an expanded population
of specific T cells, which, in the presence of antigens,
produce cytokines locally. These cytokines attract
monocytes from the bloodstream into the lesion and
activate them. DTH is immunologically a process sim-
ilar to cell-mediated immunity, involving T cells and
cytokines. However, DTH leads to pathologic re-
sponses, such as granulomatous inflammation, calcifi-
cation, caseation necrosis, and cavity formation. DTH
is also required for host defense against the etiologic
agents. The expression of cell-mediated immunity/DTH
is a double-edged sword that may contribute to both
clearance of etiologic agents and tissue damage.
ACKNOWLEDGMENTS
This work was partly supported by grants from the
Ministry of Health, Labour and Welfare (Research on
Emerging and Re-emerging Infectious Diseases,
Health Sciences Research Grants) and Ministry of the
Environment (Global Environment Research Fund).
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