Methods of treatment of disease using adsorbent carriers

Details Methods of treatment of disease using adsorbent carriers Methods of treatment of disease using adsorbent carriers

2000-11-17

2002-12-24

Park, Hankyel T. (Department: 1648)

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

Involving virus or bacteriophage

C604S004010, C604S005010, C604S005020, C604S006010, C604S006030, C424S208100, C424S228100, C424S248100, C422S105000, C210S435000, C210S090000, C210S263000, C210S502100, C210S500300, C210S645000

Reexamination Certificate

active

06498007

ABSTRACT:

TECHNICAL FIELD
This invention relates to a method involving blood leucocyte apheresis for treatment of disease.
BACKGROUND ART
For some time, therapeutic apheresis has been known as an alternative strategy for the management of disorders. The technique involves the removal of cells or proteins that are implicated in the pathogenesis of the disorder, for example rheumatoid factor, immune complexes and other humoral mediators in the plasma (1, 2). Procedures employing selective removal of blood cells or plasma components, without the use of replacement fluids, are associated with minimal side effects (1). An outpatient approach is possible, which is more convenient for the patient and reduces the cost of the procedure (2). Many of the unacceptable side-effects of chronic drug therapy are also reduced by use of the technique.
In EP-A-0-319961 there is described a method for the selective removal of granulocytes from blood by bringing the blood into contact with an adsorbent carrier having a higher affinity for granulocytes than for lymphocytes. That invention is concerned with cancer treatment. An apparatus for carrying out the method is also described in that application. A similar apparatus is described in U.S. Pat. No. 5,725,768.
In JP 0193 481 and U.S. Pat. No. 5,567,443 there is described a method for the treatment of inflammatory disease which comprises bringing blood from a patient into contact with an adsorbent carrier that has an affinity for inflammatory cells (granulocytes and monocytes) which is greater than its affinity for lymphocytes. The method is reported to be useful for treating acute respiratory distress syndrome, rheumatoid arthritis, autoimmune diseases, allergic diseases and reflow disorders following myocardial infarction.
AIDS is a life-threatening immunodeficiency condition caused by HIV (human immunodeficiency virus). After confirmation and onset of HIV infection, the mortality rate is very high. No effective treatment strategy has been established yet for the treatment of AIDS and, owing to a long latent period, it is also difficult to establish an effective measure for the prevention of infection.
After infection with HIV, anti-HIV antibody appears in the blood, generally within 6 to 8 weeks. Deficiency of or disturbance to the immune system proceeds, leading eventually to AIDS. For convenience, the intermediate stage is classified as AIDS related complex (ARC). Certain cells infected with HIV harbour the virus and act as reservoirs of the HIV. Such cells include mononuclear cells (monocytes/macrophages) and resting CD4
+
lymphocytes. While the virus is inside those cells, it is protected from clearance by the immune system. The virus is also shielded from contact with administered drugs so effective treatment of the condition is thus difficult.
The main symptoms of AIDS include fever, persistent systemic lymphadenoma, weight loss (cachexia) and diarrhoea. In addition, opportunistic infectious diseases and malignant tumours may develop and profoundly aggravate the patient's condition. Neuropathy may also become a serious problem and, depending on the patient, a disease of the cranial nervous system may also appear.
Based on an immunological consideration of full blown HIV-induced disease (AIDS), the condition is characterised by a profound impairment of the immune response, including decline in CD4
+
T lymphocytes, dysregulated cytokine production, increased production of proinflammatory or immunosuppressive cytokines such as TNF-&agr;, IL-1&bgr;, IL-6 and IL-10 by peripheral blood cells (3-6) including monocytes (3) and also by granulocytes (4) and enhanced susceptibility of immune cells to apoptosis. HIV antigens such as gp120 bound to immune complexes are believed to induce apoptosis of CD4
+
cells (7-12). TNF-&agr;, IL-1&bgr;, IL-6 are reported to promote HIV replication (3). At the same time, there is a profound impairment of the ability of monocytes from HIV-infected patients to generate IL-12 (an immunoregulator cytokine). Thus, in healthy individuals, monocytes mainly produce IL-12, whereas in HIV-infected individuals, monocytes produce mainly IL-10. IL-10 was shown to have a pivotal role in the aforementioned changes in the production of cytokines (5, 6). In this context, it is also important to indicate that IL-2 and IL-12 reduce, whereas IL-10 increases susceptibility of CD4
+
cells of HIV-infected patients to apoptosis (13-17).
Currently, the treatment strategy for HIV infection consists primarily of highly active antiretroviral drug therapy (HAART) which includes a protease inhibitor. However, whilst in some patients, HAART has been shown to increase CD4
+
cell count and to suppress plasma HIV viral load to undetectable levels, as yet no drug treatment is known to affect cellular reservoirs of HIV, for example, in cells including mononuclear cells (monocytes/macrophages) and resting CD4
+
lymphocytes. These cells serve as sites for an HIV reservoir and as sites for HIV replication and dissemination. This means that when drug treatment is ceased, there is a very strong possibility of relapse attributable to HIV propagation from the aforementioned reservoir cells and de navo infection. In the light of this understanding and for complete eradication of HIV, it is considered to be essential to eliminate the infected resting cells (latent HIV reservoirs). However, at present, there is no drug that can affect the cellular HIV reservoirs, the HIV-1 proviral DNA load in the latently infected mononuclear cells (monocytes/macrophages) and resting CD4
+
lymphocytes.
The hepatitis C virus (HCV) infects cells, for example liver cells, and subsequently harbours in those cells and in leucocytes during an apparently latent period. At present, there is no drug that can affect the cellular HCV reservoirs in those latently infected cells.
Mycobacterium leprae
infects and then remains in mononuclear cells. Present drug treatments are largely ineffective against the organism when inside the cells.
The present invention is based on the surprising observation that leucocytes infected with HIV can be selectively removed from blood.
DISCLOSURE OF INVENTION
The present invention provides a method for the removal of infected, activated and/or defective leucocytes from blood, which comprises bringing blood that comprises infected, activated and/or defective leucocytes into contact with an adsorbent carrier that has a greater affinity for infected, activated and/or defective leucocytes than for uninfected, non-activated or non-defective leucocytes. If desired, the treated blood may be returned to the subject from whom it was obtained.
The method of the present invention effects selective adsorption of infected, defective and activated leucocytes including mononuclear cells i.e. monocytes/macrophages, and also activated lymphocytes, for example CD4
+
lymphocytes, including resting CD4
+
lymphocytes. Normal, that is to say, non-infected, non-activated and non-defective leucocytes do not appear to adhere to the adsorbent carrier. This is surprising, as the previous uses of apheresis were based on the fact that granulocytes or inflammatory cells, classified as granulocytes and monocytes, were selectively adsorbed in preference to lymphocytes. Contrary to the previous observations that selective adsorption is based on cell type, we have now found that infection of a leucocyte with a virus, which is an intracellular parasite, activation of a leucocyte and/or defects in a leucocyte brings about adsorption to an apheresis column regardless of the leucocyte type.
We presently believe that infection results in selective binding of a population of leucocytes to an adsorbent carrier. We believe that this is owing to a change in a property of the leucocytes, for example a change in the cell surface receptor population, for example a change in receptor types or receptor numbers. A change caused to a leucocyte by infection may be considered as activation of the leucocyte, or the leucocyte may be regarded as defective. Ho

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