Stopping Autoimmunity at its Roots: New Advances in the Treatment of Lupus Nephritis

Autoimmune diseases are the result of our own immune systems turning against us. There are various mechanisms through which autoimmunity can develop, most of which involve the breakdown in peripheral tolerance, which are the mechanisms our body puts in place to keep autotreactive T and B cells from damaging self tissue. If an autoreactive lymphocyte escapes central tolerance and finds its way to the periphery, it becomes the job of regulatory T cells (Treg cells) or tolerogenic DCs to anergize or delete the autoreactive lymphocyte. If there are abnormalities in regulatory T cells, then peripheral tolerance is hindered and an autoimmune disease could develop. Other conditions could result if problems exist in compliment deposition since C3b is responsible for helping immune complexes remain soluble when they pass through narrow channels in the body’s periphery. When cells are destroyed during an autoimmune attack, internal cell contents can be leaked and then work as antigens for the activation of additional lymphocytes. This occurrence may perpetuate an autoimmune response. Regardless of the mechanism, these responses are damaging to the host and require the development of effective treatments.

One damaging autoimmune disease, systemic lupus erythematosus (SLE), is caused by the production of “antinuclear” antibodies which target internal cell components such as DNA when these molecules are released from cells. This disease can affect the skin, joints, kidney, lung, heart, and brain. Since SLE’s symptoms are often varied, the disease can be mistaken for other illnesses. The mechanism of action of SLE has been linked to abnormal B cell development and activation. These B cells are also more sensitive to cytokines than would normally be expected. Furthermore, the fact that an increase in IL-10, a B-cell stimulating molecule, has been associated with SLE patients provides additional evidence that this disease is caused by B cells. This observation is interesting because typically we associate IL-10 as an immunosuppressive cytokine, however in the case of SLE patients, the immunostimulatory effects of IL-10 on B cells appear to outweigh its immunosuppressive value (1). SLE is considered to be a type-III hypersensitivity because these activated B cells produce autoantibodies that can form insoluble immune complexes that basically “clog up” narrow capillaries or other parts of the body such as the glomerulus, a spherical structure in the kidneys which filters blood. As a result, many SLE patients manifest the serious disorder called lupus nephritis. Lupus nephritis is a major cause of morbidity and mortality among SLE patients (2). It results when immune complexes interfere or cause damage to structures in the kidney, such as the glomerulus, and can rapidly worsen to kidney failure. Treatment for lupus nephritis typically focuses on the use of medications to suppress the immune system in order to improve kidney function. Dialysis, to control symptoms of kidney failure, and kidney transplantation are other treatments that may be recommended.

Recent research by K. Ichinose and several colleagues at Beth Israel Deaconess Medical Center and Harvard Medical School has been focusing on the cause of lupus nephritis rather than on new treatments for the malady. The researchers are hoping that their efforts will lead to the development of a more targeted drug which can do more for patients than the current drugs that work by suppressing the immune system on a large scale. They chose to study mesangial cells (MC’s) in the glomerulus because they proliferate during lupus nephritis, a phenomenon that could link MC’s to the cause of this autoimmune disease. Typically, the function of these specialized cells is related to support, filtration, and phagocytosis of immunoglobulin. These cells can also produce the proinflammatory cytokine IL (interleukin)-6, found during glomerular inflammation. The researchers also looked at calcium/calmodulin-dependent kinase type IV (CaMKIV). This kinase belongs to a family of kinases that regulates autoimmunity and cell proliferation. CaMKIV is a multifunctional protein that is highly expressed in the central nervous system. Because increased expression of CaMKIV has been linked to certain cancers, some researchers see this as evidence that it is involved in cell proliferation (3). This observation led them to perform tests to ascertain whether CaMKIV could be deleted or its actions blocked, possibly leading to decreased MC proliferation and IL-6 production that could in theory alleviate an autoimmune response.

Immunotherapy: Giving Our Bodies a Boost to Fight Infection

The human body’s immune system works tirelessly to keep us healthy. So wouldn’t it be nice if we could lend it a hand in its effort to rid our bodies of all types of pathogens and cancers? Immunotherapy is a type of treatment that seeks to augment our own body’s immune system as it battles certain illnesses and physical conditions. Applications of immunotherapy have been found to be significant in the treatment of cancer, AIDS, autoimmune diseases, and in protecting the body following organ transplantations.

Immunotherapy can be broken down into two main categories: active immunotherapy and passive immunotherapy. Active immunotherapy is designed to stimulate our own immune system so that it can be more effective in combating a disease, such as a cancer vaccine. On the other hand, a passive immunotherapy uses artificially produced components of the immune system, such as antibodies, as a form of treatment. Playing an important role in immunotherapy are certain molecules known as immunomodulators. These molecules, including IL-2, IL-7, IL-12 and interferon, interact with the immune system to induce, enhance, or even suppress the actions of the immune system. More specifically, IL-2 can enhance T, B, and NK cell activation, while IL-7 can promote the development of lymphoid progenitor cells from hematopoietic stem cells. IL-12 is important for the differentiation of ThO cells from naïve T cells and interferon improves antiviral responses. In order to develop new kinds of immunotherapy, researchers must first acquire a sound understanding of how the immune system functions as well as the nature of the particular illness being confronted.

Debunking the Doublet: Study Finds Lack of Suggested Relationship Between IL-7 and CD4 T Cell Populations in Longitudinal Assessment of HIV Patients

Seventy-two patients with HIV participated in a recent study done by the European Union to investigate the correlation between IL-7 and CD4 T cell population density. The results of the study will be published in the December 15, 2011 edition of the Journal of Acquired Immune Deficiency Syndromes (vol 58, issue 5, pages 436-441), but is published in advance online. Thirty of the patients did not use anti-retroviral drugs and forty-two did, making up the two populations used in the study. T cell and IL-7 counts were taken regularly for 46 +/- 14 months in the two populations. The researchers then used multi-variable linear regression analysis to analyze the statistical significance of the potential IL-7/CD4 T cell correlation.

HIV is an acronym for Human Immunodeficiency Virus, a retrovirus that infects humans and is transferred through the direct sharing of bodily fluids through sexual intercourse, blood transfusions, or the sharing of syringes. There is no known cure or vaccine for HIV, and there are several challenges that make such a necessary product difficult to formulate. Primarily, HIV is a quickly mutating virus, which ensures that the virus readily mutates to avoid any single drug that is aimed against it. Another difficulty encountered when attempting to make and test a potential drug is that there currently exists no appealing animal model in which to test HIV treatments and vaccines. Chimpanzees respond to SIV, a virus similar to HIV but that infects chimps, but they never progress to AIDS. Also, chimpanzees are an endangered species, which makes using them as an animal model ethically questionable and difficult to obtain approval for.

Cytheris, a biopharmaceutical company that works with immune enhancement, has had success in mouse trials using IL-7 to treat HIV, and is currently working on Phase I clinical trials with a new HIV drug based on these results.¹ This has led to much investigation of the link between IL-7 and HIV, one outcome of which is this study. CD4 T cells are often the first immune system element that comes to mind when pondering HIV, as these are the main targets of the virus. HIV infects and brings about the death of CD4 “helper” T cells, and when the CD4 T cell count falls below 200 cells per cubic mm of blood the patient is considered to have progressed from HIV to AIDS. Thus, CD4 T cells were suggested as the link between HIV treatment and IL-7. However, the perhaps most likely link between IL-7 and the treatment of HIV, CD4 T cells, did not produce the expected results.