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Immunoglobulins, produced by B-lymphocytes, are the main mediators of humoral immunity, and deficiencies at this level affect the body's response to infection. The manipulation of immunoglobulin status in the treatment of human diseases consists of two main routes that have the purpose to augment the concentration and alter immunoglobulin in the affected host. On one hand lies the external administration of human immunoglobulin in patients that are completely deficient or compromised and are considered to benefit widely from an intravenous infusion. The other is the manipulation of immunoglobulin production via indirect immunization (vaccination) that forces the human body to produce a series of immunoglobulins that are antigen specific for the particular antigen administered via the vaccination route. Immunosupression (i.e. the lowering of the innate immune response) has been widely used in cancer therapeutics and is discussed last.
IV ADMINISTRATION OF IMMUNOGLOBULIN (passive immunization)
The U.S. Food and Drug Administration (FDA) have approved intravenous supplementary immunoglobulin treatments for a series of well-defined diseases such as: primary immunodeficiency, immune-mediated thrombocytopenia, Kawasaki disease, haematopoietic stem cell transplantation (in patients > 20 years), chronic B-cell lymphocytic leukemia, and HIV in children. However, immunoglobulin products which are mainly sterile, purified immunoglobulin G (IgG) derived from a pool of donors (usually 3,000-10,000) are also commonly used throughout the world for the treatment of various other diseases such as idiopathic diseases (unknown cause diseases such as recurrent abortions) and infections.
The therapeutic use of immunoglobulin IV treatments consists mainly of providing with an increased protection versus infection for immunocompromised patients, may also help prevent patients with Kawasaki disease from developing coronary artery aneurysms or increase the number of platelets in patients who have life threatening idiopathic thrombocytopenia purpura (ITP) and prolong sustaining of grafts in transplant surgery (Shehata et al, 2010).
However, the fact that the immunoglobulin is gathered through a pool of donors, poses a significant infection threat to the infused individuals. Although the risk for HIV and Hepatitis B transmission remains low due mainly to obligatory testing since 1995, the risk for acquisition of several other viruses and bacteria, or even smaller life forms such as prions and mycoplasma is considered significant (Carbone, 2007). Moreover, the transfused immunoglobulin is not 100% pure, since it often contains small amounts of cytokines, CD4 cells, CD8 cells, and human leukocyte antigens (HLA). All the above blood products are known to produce and attenuate a significant inflammatory reaction to the infused host, and currently the effects caused by these by products of immunoglobulin treatments is not sufficiently elucidated.
IgG has a half-life in the circulation of approximately 21 days, so intravenous infusions of approximately 600 mg of IgG per kg body weight given every 3 to 4 weeks maintain an IgG level of approximately 500 mg/dl (approximately 50% of levels in healthy adults (Quartier,1999). Activation of inflammatory pathways by the infusion process (infusion related reaction) or by complexes formed by antibody binding within the recipient host seems a likely mechanism for the adverse effects mentioned above. The rate and severity of reactions to intravenous formulations of IgG are greatly reduced by slowing the rate of infusion and by administering a prophylaxis with paracetamol and an antihistamine. However, its use is still not accepted in many cases with the example of a Cochrane Systematic Review (Ohlsson , 2010) that has recently concluded that there is still insufficient evidence to support the routine administration of IVIG in infants with suspected or subsequently proved neonatal infection. For cases such as primary deficiency where immunoglobulins act as replacement therapy and are absolutely indispensable for survival, new IVIGs have been developed such as the Flebogamma 5% IVIG treatment( Ballow, 2009), which is considered to further enhance the pathogen safety margin due to pasteurization and pore microfiltration.
Recent advances in vaccination include the amelioration of viral-vector vaccines that nowadays remain the best means to induce cellular immunity and are showing promise for the induction of strong humoral responses. Targets range from certain types of cancer to a vast array of infectious diseases (Draper and Heeney, 2010). The main problem with this design is that the innate immune system readily recognises the viruses and viral vectors used in the vaccine preparation that renders this means unsafe for wider use, such as gene therapy (Huang, 2009).
The emergence of biological materials that can affect the immune system is a developing field alongside immunology. These materials can deliver antigens through specific intracellular pathways, allowing tight control of the way antigen presentation to T cells. Materials are also being designed as adjuvants, to mimic specific 'hazardous' signals in order to manipulate the resultant cytokine environment, which influences how antigens are further interpreted by T cells.
The development of prophylactic vaccines against human papilomavirus has been hailed as one of the most significant advances of recent years by most communities and researchers and it is expected to dramatically reduce the mortality in HPV associated cervical and anal cancers, but has also given rise to rigorous scientific debate (Hampl, 2009).
In haematological malignancies, the spread of use of a different type of vaccination is idiotype B-cell vaccination. Each patient's B-cell malignancy is usually derived from a single expanded B-cell clone, which expresses an immunoglobulin (Ig) with a unique idiotype (Id, variable regions of Ig). Therefore, this idiotype can be regarded as potential target in clinical cancer vaccination approaches against the clonal B cell line. Currently it is a non-approved, experimental therapeutic option for patients with lymphoma and myeloma. The applicability of Id vaccines for B-cell malignancies such as chronic lymphocytic leukemia, mantle cell lymphoma and multiple myeloma needs to be further tested (Inoges, 2010).
OTHER TYPES OF IMMUNOMODULATION
Systemic immunomodulation, also known as adjuvant therapy, has been a treatment modality in a variety of clinical diseases to boost the immune response even though the antigens are not always known or are ill defined. Systemic immunomodulation frequently results in unwelcome effects, most notably autoimmune disease activation.
The therapies include:
In the past several decades, IFN has emerged as a major therapeutic modality for several malignant and non-malignant diseases, including hepatitis C, carcinoid tumors, hairy cell leukemia, and Kaposi's sarcoma. However, apart from the wide side-effect range profile, IFN is also found to induce autoimmune responses with the production of autoantibodies mainly autoimmune thyroid disease (ATD) and thyroiditis (Kong et al, 2009),(Tomer, 2007).
IL-2 is used for the treatment of metastatic melanoma. Similar to IFN, IL-2 has been reported to induce the development of several autoimmune conditions, most notably ATD.
To enhance the immune response to a peptide vaccine derived from a family member of human epidermal growth factor receptor (Her-2/rat neu) in prostate cancer patients, human recombinant flt3 ligand, a growth/differentiation stimulator for dendritic cells, is used as a systemic adjuvant. It is unknown whether the Flt3 ligand can also induce autoimmunity.
Monoclonal antibodies (MoAbs) have been introduced for the treatment of various cancers, and their ability to bind to any specific target within the body is then used favourably in therapeutics to direct an immune response against the binding tissue site. A recent review has found little to no infectious complications to their use in various types of malignancies, although allogeneic in nature (Rafailidis et al, 2007).
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