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
1999-06-17
2002-03-12
Saunders, David (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...
C424S193100, C424S227100, C514S049000
Reexamination Certificate
active
06355248
ABSTRACT:
FIELD OF THE INVENTION
The field of the invention is modulation of the immune response of a mammal infected with an infectious agent.
BACKGROUND OF THE INVENTION
Numerous bacterial, viral, and parasitic infections of mammals have two phases of infection: an acute phase during the early stages of the infection, sometimes followed by a prolonged chronic phase having a finite or indefinite duration. The ability of an infectious agent to establish a chronic infection in a mammalian host depends to a significant extent on the capacity of the host immune response to eliminate the infecting organism from the host in the early stages of the infection. The specific immune mechanisms responsible for eliminating the infectious agent from the host differ depending on the infectious agent. In the case of viral and some parasitic infections, the infectious agent-eliminating activity of cytotoxic T lymphocytes is believed to comprise a pivotal component of the host immune response for mediating the elimination of these agents from the host.
The components of a mammalian immune system to which mammalian immune response activities can be attributed include, but are not limited to, antibody molecules, complement molecules, B lymphocytes, T lymphocytes, cytotoxic T lymphocytes, helper T cells, suppressor T cells, immunosuppressive lymphocytes, cytokine-secreting lymphocytes, other non-cytotoxic lymphocytes, macrophages, neutrophils, mast cells, basophils, eosinophils, monocytes, and the like. Induction or replication of the host immune activities leading to complete elimination of an infectious agent from a mammalian host is the paradigm for a clinical treatment for infection by a infectious agent.
In the course of infections with bacteria and some parasites, elimination from a host of an infectious agent causing an acute infection has traditionally been accomplished using antibiotics which serve as relatively selective poisons for the infectious agent. Antibiotic treatment has been less successful in the case of chronic bacterial infection. More recently, clinical efforts have focused on modulating the host immune system in an attempt to eliminate infectious agents causing chronic infections in cases wherein indolence of the host immune system contributes to persistence of the infectious agent. Specific immune modulation using substances such as interferons alpha, beta, and gamma has been attempted, and in a minority of cases beneficial results have been observed.
When an infection becomes chronic, the infection may be controlled by a persistent host immune reaction to the infectious agent. Certain herpes viruses, for example, remain latent only in the context of host immune competence. Immunosuppressive therapy used, for example, in organ transplant recipients permits latent herpes virus to become reactivated. Thus, loss of immune competence in response to steroid and cyclosporin A administration to a human patient having a latent HHV-6 infection permits recrudescence of HHV-6. The result of HHV-6 reactivation includes viral pneumonia and bone marrow suppression. In addition, the high incidence of non-Hodgkins B cell lymphomas among humans infected with the AIDS virus (HIV-1) demonstrates that pathogenicity attributable to chronic Epstein-Barr virus infections becomes active as T cell competence is lost. Thus, reactivation of pathogenicity attributable to an otherwise non-pathogenic chronic infection which is effected by suppression of the host's immune competence may have deleterious effects on the host.
Several microbial infectious agents cause disease in a mammalian host predominantly by eliciting a host immune response which is ineffective in eliminating the infectious agent from the host, but is effective in damaging or destroying host tissues. One such virus which functions in this manner is the AIDS virus, HIV-1. HIV-1 mediates destruction of helper T lymphocytes in HIV-1-infected humans, but the mechanism of cellular destruction has not been unequivocally defined. Although helper T cells are destroyed in culture by syncytium formation, the presence of multinucleated T cells in patient samples has not been reported. This suggests that in vivo syncytium formation is a rare event. It is known that patients infected with HIV-1 develop a strong cytotoxic response to the virus, and that this response persists throughout the course of the infection. It is also known that at least some of the T cell loss characteristic of AIDS is the result of the death of CD4-bearing T cells which express viral antigens within the context of MHC class I molecules. The death of these cells is mediated by the immune system in the infected individual.
HTLV-I, another human retrovirus, does not directly damage host cells. Patients chronically infected with HTLV-1 frequently exhibit a slowly developing neurological disease, namely HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP). HAM/TSP is clinically and histopathologically similar to the human autoimmune disease, multiple sclerosis (MS).
In humans afflicted with MS, neural elements are lost, apparently due to the immune reactivity of the patient to viral antigens in the neuropil. It has been suggested that MS has an infectious etiology. Although several viruses have been suggested to be the pathogenic trigger for the development of MS, recent experimental evidence strongly suggests that human herpesvirus 6 (HHV-6) may be the infectious agent ultimately responsible for development of MS in humans. Replicating HHV-6 has been identified in MS plaques (Challoner et al., 1995, Proc. Natl. Acad. Sci. USA 92:7440-7444). Furthermore, the majority of humans having the relapsing-remitting form of MS exhibit evidence of an immune reaction to acutely replicating HHV-6 (Soldan et al., 1997, Nature Med. 3:1394-1397). These observations suggest that MS, which has long been classified as an autoimmune disease, may result from chronic infection of a human with HHV-6. If this is true, a human afflicted with MS would benefit from suppression of the immune response to the presence of HHV-6 in the human.
Certain chronic bacterial and protozoal infections also mediate disease in a mammalian host by inducing persistent host immune reactivity coupled with ineffective elimination of the infectious agent from the host. For example,
Mycobacterium tuberculosis
is a slow growing organism which causes tissue destruction primarily via the host autoimmune response. Similarly, the protozoan
Leishmania donovani
is itself relatively non-pathogenic, but a persistent host immune reaction to infection results in severe disease. Lymphatic filariasis leads to partial occlusion of the lymph channels, but the contribution of the persistent ineffective immune reaction to the parasite is also responsible for the loss of lumen patency with the resulting disfiguring elephantiasis. Mammalian infection by
Leishmania braziliensis
frequently leads to severe mutilating facial lesions which appear years after the original facial lesion has healed. The severe lesions are caused by repeated attempts by the immune system to destroy small numbers of the parasite remaining in the host. Similarly, parasites such as
Schistosoma mansoni
cause scarring of the hepatic portal tracts by inducing a persistent immune reaction to parasites dwelling within the liver. The immune reaction does not clear the infection, circulatory difficulties result, and life threatening cirrhosis with portal hypertension may ensue.
Perhaps the most illustrative example of a class of infectious agents that are intrinsically non-pathogenic in the absence of a persistent immune response is hepatitis B virus (HBV). Most individuals who become infected with HBV exhibit few clinical symptoms and eliminate the virus from their system within several weeks following exposure. About 10% of acutely HBV-infected individuals develop chronic infection. The factors which predispose individuals to chronic infection are largely unknown. HBV is ubiquitous, and the worldwide population of chronically HBV-infected individuals has bee
Block Timothy
Michaels Frank
Drinker Biddle & Reath LLP
Saunders David
Thomas Jefferson University
Tung Mary Beth
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