Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Amino acid sequence disclosed in whole or in part; or...
Reexamination Certificate
1998-07-17
2003-02-11
Nolan, Patrick J. (Department: 1644)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Amino acid sequence disclosed in whole or in part; or...
C424S184100, C424S185100, C424S193100, C424S194100
Reexamination Certificate
active
06517839
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to the fields of medical microbiology and immunology. More particularly, the invention provides methods for inducing the production of interleukin-12 in peripheral blood mononuclear cells and, thereby, inducing a type 1/Th1 T cell immune response that is central to an effective cell-mediated immune response to intracellular pathogens or interferon &ggr;-sensitive tumors.
BACKGROUND OF THE INVENTION
Infection with the intracellular pathogen
Mycobacterium tuberculosis
(
M. tuberculosis
) continues to produce great morbidity and mortality throughout the world with 8 million new cases of tuberculosis and 3 million deaths occurring annually. Such creates an urgency to understand mechanisms of cell-mediated immunity (CMI) to the infection (Bloom and Murray,
Science
257: 1055-1064, 1992). The spectrum of clinical outcomes after infection with
M. tuberculosis
is determined largely by the interaction of T-cells and monocyte/macrophages. Two functionally distinct subsets of T-cells modulate the outcome of such intracellular infections (Mosmann et al.,
J. Immunol
136:2348-2357, 1986). In human infectious disease, Type 1 T-cells that produce interleukin-2 (IL-2) and interferon &ggr; (IFN-&ggr;) activate macrophages to kill or inhibit the growth of pathogens, resulting in mild or self-curing disease (Yamamura et al.,
Science
254:277-279, 1991; Salgame et al.,
Science
254:279-282, 1991). In contrast, type 2 T-cells which produce interleukins-4, -5, and -10 (IL-4, IL-5, IL-10) augment humoral responses (circulating antibody responses) and inhibit CMI, resulting in fulminant disease. The differentiation of naive T-cells into producing either type 1 or type 2 cytokine profiles is shaped by the cytokine milieu produced by the surrounding monocytes and macrophages. In particular, interleukin-12 (IL-12) is a key bridge between the innate immune response of monocyte/macrophages and the adaptive immune response of type 1 T-cells (Romagnani, S.,
Immunol Today
13:379-381, 1992).
IL-12, a cytokine or hormone-like substance, is produced by activated monocytes as a heterodimeric protein composed of p35 and p40 subunits. The p40 subunit is inducible and is considered to be the regulatory component for IL-12 expression (D'Andrea et al.,
J Exp Med
176:1387-1398, 1992). IL-12 production in response to microbial pathogens leads to activation of natural killer (NK) cells and T-cells with ensuing production of IFN-&ggr;. In the presence of high IFN-&ggr; and low IL-4, there is subsequent development of a type 1 T-cell cytokine response and vigorous CMI (Hsieh et al.,
Science
260:547-549, 1993; Gazzinelli et al.,
J Immunol
153:2533-2543, 1994; Heinzel et al.,
J Exp Med
177:1505-1509, 1993).
In animal models of infection due to intracellular pathogens, the production of IL-12 is important in the generation of protective, Th1-mediated, immunity (Scott et al.,
J Exp Med
168:1675-1684, 1988; Heinzel et al.;
J Exp Med
169:591989; Liew et al.,
Eur J Immunol
19:1227-1232, 1989; Sadick et al.,
J Exp Med
171:115-127, 1990). For example, in mycobacterial infection, IL-12 production at the site of disease is a prominent characteristic of the resistant phenotype or self-limited disease. In tuberculosis, IL-12 has been found in the pleural fluid of patients with tuberculous pleuritis; and, anti-IL-12 antibodies partially inhibit the proliferative response of the pleural fluid lymphocytes to
M. tuberculosis
(Zhang et al.,
J Clin Invest
93:1733-1739, 1994). In leprosy, IL-12 induces the expansion of mycobacteria-reactive T-cells which produce IFN-&ggr;, but has little effect on T-cells which produce IL-4 (Sieling et al.,
J Immunol
153:3639-3647, 1994). Further, in a murine model, exogenous administration of IL-12 increases the resistance of mice to
M. tuberculosis
infection via the IFN-&ggr; pathway (Flynn et al.,
J Immunol
155:2515-2524, 1995; Cooper et al.,
Immunology
84:423-432, 1995). In addition, production of IFN-&ggr; is required for immunity to mycobacterial infection (Flynn et al.,
J Exp Med
178:2249-2254, 1993; Cooper et al.,
J Exp Med
178:2243-2247, 1993).
A number of prokaryotic lipoproteins reportedly are potent macrophage stimulators. Examples include the TraT and Braun lipoproteins of
E. coli
, the outer membrane proteins of
Treponema pallidum
and
Borrelia burgdorferi
, and a lipoprotein of
Mycoplasma fermentans
. The
B. burgdorferi
OspA antigen and the 47 kDa antigen of
T. pallidum
have been reported to induce IL-12 mRNA (Ma et al.,
Infect Immun
62:3663, 1994; Radolf et al.,
J Immunol
154:2866, 1995).
The nature of an immune response reflects the profile of antigen-specific lymphocytes that are stimulated by the immunization. T cells consist of subpopulations that may be stimulated by different types of antigens and perform different effector functions. For example, in viral infections, viral antigens are synthesized in infected cells and presented in association with class I major histocompatibility complex (MHC) molecules leading to stimulation of CD8+, class I MHC-restricted cytotoxic lymphocytes. In contrast, extracellular microbial antigens are endocytosed by antigen presenting cells, processed, and presented in association with class II MHC molecules. This activates CD4+, class II MHC-restricted helper T cells, leading to antibody production and macrophage activation but relatively inefficient development of cytotoxic lymphocytes.
IL-12 promotes the development of Th1 cells, and microbes that stimulate macrophages to produce IL-12 or natural killer (NK) cells to produce IFN-&ggr; induce Th1-dominated responses. A type 1/Th1 T-cell response is where CD4+ helper Th1 cells secrete interleukin-2 and interferon-&ggr; which activates macrophages and are the principal effectors of cell-mediated immunity against intracellular microbes and of delayed type hypersensitivity. The antibody isotypes stimulated by Th1 cells are effective at activating complement and opsonizing antigens for phagocytosis. Therefore, Th1 cells trigger phagocyte-mediated host defense.
IL-4 stimulates differentiation of CD4+ T cells toward Th2 cells, and parasites, in general, induce early IL-4 production. Th2 cells also produce interleukin-4, which stimulates IgE antibody production, IL-5, IL-10 and IL-3, which together with IL-4 suppress cell-mediated immunity. Therefore, the Th2 subset of T cells is mainly responsible for phagocyte-independent host defense, e.g., against parasites; which is mediated by IgE and for allergic reactions, which are due to IgE-dependent activation of mast cells and basophils.
Protective immunity induced by vaccination is dependent on the capacity of the vaccine to elicit the appropriate immune response to either resist, control, or eliminate the pathogen. Adjuvants are substances capable of increasing the immunogenicity of antigens; such substances include aluminum salts, bacterial endotoxins, bacillus Calmette-GuJrin (BCG), or
Bordetella pertussis
, for example. Adjuvants stimulate the immune response by combining with antigen and forming an aggregate; this aggregate acts as a depot for prolonged antigen stimulation. In experiments with animals, the most frequently used adjuvants are Freund's complete and incomplete adjuvants, which include water and oil emulsions with or without heat-killed
Mycobacterium tuberculosis
. The use of bacterial adjuvants to augment systemic immune responses in a nonspecific way is not without possible dangers. Repeated inoculation with live BCG organisms has caused systemic mycobacterial infections in several patients. To avoid this complication, other bacterial adjuvants, such as killed preparations of
Corynebacterium parvum
have been tested, and attempts have been made to extract the immunopotentiating component from BCG. In addition to prolonging antigen stimulation, adjuvants may also stimulate the immune response by influencing the cytokine milieu; activity and recruiting specific cell types, etc.
Responding to the need f
Libraty Daniel H.
Modlin Robert L.
Ewoldt Gerald R.
Mandel & Adriano
Nolan Patrick J.
The Regents of the University of California
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