IMMUNOMODULATION

What is Immunomodulation? Immunomodulation is a therapeutic approach in which we try to intervene in auto regulating processes of the defense system. Three Pillars of Homotoxicology DETOXIFICATION IMMUNOMODULATION CELLULAR ACTIVATION

Homotoxicology detoxify the body and restore the bodys natural biorhythms Basic actors of the defense scene APC - phagocytosis, present Ag to Tcell Dendritic cell- stimulates and modulates cellmediated response Th0 - nave, Th1,2 - triggers and stimulate the defense against a specific antigen Th3- suppress/inhibit function of Th1 and Th2

Major Histocompatibility Complex MHC Class I - expresses the specificity of the cell and will change under influence of intruding antigens. A changed MHC class-I on the cell will trigger natural killer cells (NK cells) and cytotoxic cells (cT cells) to correct or eliminate the affected cell. MHC Class II - Once the defense cell has a changed MHC class-II nave T-lymphocytes are attracted chemotactically to take over the characteristic motif of the phagocytosed antigen. In thus the specific defense against the antigen is triggered and set on. Dehydroepiandrosterone-mother of hormones, stimulates cellular immunity or skewing of TH-1 mediated reaction in the balance long term secretion of cortisol (e.g.stress) will induce a skewing at the TH-2 side of the balance inducing allergies, some auto-immune diseases and even cancer

TH1/TH2 switch TH1 rigidity Cellular autoimmunity, e.g., Rheumatoid arthritis, Multiple sclerosis Chronic recurrent inflammation Tendonitis Cardiomyopathy Crohns disease TH2 rigidity Allergic diseases Asthma Eczema Allergic rhinitis Cellular immune dysfunction Chronic fungal disease Chronic fatigue syndrome Cancer Late AIDS Recreational Drugs Ecstasy Alcohol

Cytotoxic T Lymphocyte Antigen 4 (CTLA-4) and CD28 are also important regulators of T lymphocyte activation. Once activated CTLA4 avoids that another than the initial antigen triggers the T-cell again which keeps the task specific. CTLA-4 seems to play an important role in self tolerance. When the APC presents own protein to the immune system the binding of CTLA-4 will cause the T-cell to die (apoptosis), and not to react.

TH1/TH2 balance TH-1 cells are responsible for the cellular immunity. They trigger natural killer cells (NK-cells) and macrophages micro organisms or even deviating cells from proper origin (e.g. viral infected organ cells). TH-2 cells direct humoral immunity. Once triggered by a motif on their TCR their activity results in a stimulation of antibody production (B-cells, plasma cells) so that antigens outside the cells (humoral = body liquids) are eliminated. TH-3 cells are regulator cells. Their main inflammation regulating mediator is TGF-, Transforming Growth Factor beta. Treg cells will inhibit both the TH-1 and TH-2 pathway and are therefore down regulating inflammation. In antihomotoxic medicine the stimulation of Treg cells is a common technique to intervene in inflammation processes.

A blocking in the TH-1 state will cause TH-1 rigidity. Typical diseases here are all the diseases where the immune system directs itself against proper tissues (cellular autoimmunity). Other examples are the great variety in chronic inflammations. Also cardiomyopathy and Crohns disease are a TH-1 stage rigidity. A blocking in the TH-2 stage will cause allergic diseases at different locations. Also cellular immune dysfunctions, CFS, late AIDS stage, cancer, are all TH-2 rigidity caused.

Inflammation: mediators Causes inflammation Degrade tissues Interleukin-1 Interleukin-6 Interleukin-8 Tumor necrosis factor From: Macrophages TH1 cells Chondrocytes Fibroblasts Stops inflammation Helps tissue repair Interleukin-10 Transforming growth factor From: TH3 cells IL10 Reg cells Other body cells

IMMUNODEFICIENCIES
Deficiencies of the immune system include disorders of phagocytic cells. B lymphocytes, a combination of T and B lymphocytes, and the complement system

Lazy leukocyte syndromes include: Job syndrome (hyperimmunoglobulin E) - is characterized by poor chemotaxis and recurrent skin infections and abscesses. Tuftsin deficiency. Tuftsin is a chemotaxin that also improve phagocyte motility, engulfment and oxidative metabolism. Affected persons experience recurrent bacterial infections. Actin dysfuncton. A deficiency of the cytoskeletal protein actin can result in decreased bacterial motility and chemotaxis. Patients experience recurrent bacterial infections.

PHAGOCYTIC CELL DEFICIENCIES

result in a decreased ability to phagocytize and kill bacteria Chronic granulomatous disease (CGD) is a genetic disease characterized by ineffective killing of bacteria by neutrophils. Cause. CGD is caused by a defect n cytochrome b, which results in decreased hydrogen peroxide production. Hydrogen peroxide is neccessary for producing thr toxic superoxides that are critical in bacterial killing. Diagnosis. The nitroblue tetrazolium (NBT) reductase test is used to detect impaired neutrophil phagocytosis. The neutrophils of CGD patients fail to reduce the NBT dye. Symptoms. Patients with CGD suffer from recurrent infections caused by catalase-positive bacteria and yeast and fungi. Treatment includes the use of GSM-CSF or G-CSF and IFN-y.

B-LYMPHOCYTE IMMUNODEFICIENCIES
may be inherited or acquired and account for more than half of all immunodeficiencies. Affectedness varies widely, depending on the class of immunoglobulin that is deficient. A deficiency of a minor immunoglobulin, such as IgD, causes little if any increase in the incidence of bacterial infections. However, because 75% to 85% of total immunoglobulin s IgG, an individual deficient in IgG would be significantly affected. Brutons agammaglobulinemia - is a sex-linked disorder that primarily affects men. It is usually recognized early in life when antibodies fail to develop. Pre-B cells may be found in the bone marrow, but they do not mature. Few mature B cells are found in the peripheral blood. Gamma globulin levels are markedly decreased. This disorder may be treated with gamma globulin preparations. Common variable hypogammaglobulinemia - is an acquired disorder in which one or two immunoglobulin classes are deficient. Total immunoglobulin levels are normal, because a decrease in one immunoglobulin is often compensated by an increase in the production of another. Selective IgA deficiency is one of the most common of these deficiencies. Typically, only those patients whose disease includes IgG deficiency suffer from increased bacterial infections. Neonatal hypogammaglobulinemia - is caused by the normal immaturity of the neonates immune system. It corrects itself between the ages of 6 and 12 months as infants immune system matures.

MPO deficiency - is inherited as an autosomal recessive trait and is one of the most common inherited disorders. The MPO in the primary granules of neutrophils is decreased or absent, and although phagocytosis takes place normally, bacterial killing is inefficient. Fungal killing is more seriously impaired than bacterial killing. Although otherwise healthy patients with MPO deficiency do not have an increased frequency of infection, diabetic patients who have this disorder may have an increase in Candida sp infections. Glucose-6-phospate dehydrogenase (G6PD) deficiency- is another inherited disorder in which the aerobic system of neutrophils is impaired. This deficiency results in a substantial decrease in the amount of hydrogen peroxide produced during phagocytosis, and thus decreased bacterial killing efficiency. Patients with G6PD deficiency experience recurrent bacterial infections. CR3 (iC3b receptor) deficiency - is a rare, autosomal recessive trait characterized by a decrease or absence of specific complement component receptors on neutrophils, monocytes and lymphocytes. These receptors are responsible for adherance-related functions. Abnormalities result in defective margination and diapedesis of neutrophils, impaired chemotaxis, and ineffective phagocytosis. T lymphocytes adhere poorly to target cells. Clinically, there is an increased frequency of bacterial infections, a decreased inflammatory response, and neitrophilia. Specific granule deficiency - is inherited as an autosomal recessive trait. Neutrophils fail to develop specific granules during myelopoiesis, and as a result, patients who have this disorder experience severe recurrent bacterial infections. Chdiak-Higashi syndrome - is an inherited disorder that is characterized by the abnormal fusion of primary granules in neutrophils. During phagocytosis, degranulation is impaired, and little or no MPO s released into the phagosome. Patients who have Chdiak-Higashi syndrome have recurrent bacterial infections and are also characterized by albinism and extreme photosensitivity.

T-LYMPHOCYTE IMMUNODEFICIENCIES
without an accompanying loss of B-cell function are rare, composing only 7% of all immunodeficiencies. These disorders may be acquired or inherited. DiGeorge syndrome - results when the thymus gland develops abnormally during embryogenesis. Abnormalities of other endoderm-derived tissues are also seen. T lymphocytes are usually decreased, but may be normal. Most patients have high CD4-CD8 ratio. Although antibody responses may be normal, cell mediated immune responses are impaired. Nezelof syndrome - is an autosomal recessive disorder. Patients are arythmic and are especially susceptible to viral and fungal infections, which can be fatal in these patients.

B & T LYMPHOCYTE IMMUNODEFICIENCIES

are the most serious of the immunodeficiencies, because both cell-mediated and humoral immune responses are affected.

Bare-lymphocyte syndromes - are characterized by defects in Class I MHC antigen expression, Class II MHC antigen expression, or a combination of both. CD4-positive T lymphocytes are decreased in number, and B- and T-cell activation is reduced. Severe combined immunodeficiency disease may be inherited as autosomal recessive or X-linked traits. All are characterized by markedly decreased numbers of both T and B lymphocytes. Acquired immunodeficiency syndrome (AIDS) is caused by the human immunodeficiency virus 1 (HIV-1) or the human immunodeficiency virus 2 (HIV-2). The CD4positive T lymphocytes are the primary target cells. Approximately 5% of B lymphocytes are also infected.

IMMUNOPROLIFERATIVE DISORDERS
LEUKEMIAS malignant cells are peripheral blood. present in the bone marrow and

Acute Lymphocytic Leukemia characterized by the presence of very poorly differentiated blast cells in the bone marrow and the peripheral blood. FAB classification includes L1, L2 and L3

Chronic Lymphoid Leukemic Disorders Chronic Lymphocytic Leukemia/Lymphoma- a common hematopoeitc malignancy that involves the expansion of a clone of B cells that have the appearance of smal mature lymphocytes Prolymphocytic Leukemia- a varaiant of CLL that is composed of larger cells with round to oval nuclei and coarser chromatin pattern. Hairy Cell Leukemia- a rare, slowly progressive disease characterized by the infiltration of the bone marrow and spleen by leukemic cells, without involvement of lymph nodes.

LYMPHOMAS malignant cells arise in lymphoid tissues such as lymph nodes, tonsils or spleen Hodgkins lymphoma-chracterized by the presence of Reed-Sternberg cells in affected lymph nodes and lymphoid organs Reed Sternberg cells- large cells with a bilobed nucleus and two-prominent nucleoli (like an owls eyes) Non-Hodgkins lymphoma

Plasma cell dyscrasias- malignancies that involved the bone marrow, lymphoid organs and non-lymphoid sites that are not classified as either leukemias or lymphomas Multiple myeloma- a malignancy of plasma cells. The most serious and common of all plasma cell dyscrasias. Patients excrete Bence Jones proteins in urine. Waldenstroms macroglobulinemia - is a malignant proliferation of IgM producing lymphocytes