CaMKIV: A Potential Target for a Treatment for Lupus Nephritis

Systemic lupus erythematosus (SLE) is an autoimmune disorder that currently has no cure (PubMed Health, 2011). SLE may result in abnormal deposits in kidney cells, which leads to complications in the kidneys. This results in the condition lupus nephritis, in which extensive damage to the kidney occurs and ultimately results in kidney failure (PubMed Health, 2011). There has been much speculation that Calcium/calmodulin-dependent protein kinases (CaMKs) is a factor in the progression of SLE, for it has previously been demonstrated that CaMKIV contributes to decreased IL-2 production in SLE T cells (Karin, 1995). CaMKIV may also play a role in the production of IL-6, for it has been demonstrated that just before the age when lupus nephritis is developed, spleen cells of mice contain a subpopulation of Th cells that selectively induced their B cells in vitro to produce highly cationic IgG autoantibodies to both single-stranded DNA and double-stranded DNA (Datta, 1987). This may be of critical importance, for it has also been shown that IL-6 is a feed forward process in which macrophages respond to IgG to support further B-cell production of IgG (Maeda, 2010).

It has previously been demonstrated that inhibiting CaMKIV in lupus-prone MRL/lpr mice mitigates disease pathology (Karin, 1995). Ichinose et al. have recently elaborated on the cellular abnormalities that may be controlled by CaMKIV (2011). These results have helped to clarify the cellular processes that result in the damage of kidneys in lupus nephritis by producing large amounts of autoimmune mesangial cells and increasing production of IL-6 and have shown that CaMKIV may be a critical target in developing treatments for lupus nephritis.

Immune Mechanisms in Cardiac Graft Rejection Explored: Future Therapies In Sight

Often, when an individual has a severely damaged tissue or organ, organ transplantation by a donor may be the only option to ensure the survival of this individual. As organ transplantation procedures have become more successful in recent years, further research is being conducted to identify therapies with improved success rates of these operations. A problem often associated with allotransplantation, or the transfer of tissues or organs from one individual to another of the same species, is graft rejection mediated by the host’s immune system. Acute graft rejection often takes place in the days following a transplant, and can result in transplanted tissue damage, development of chronic graft rejection, or in the worst-case scenario, transplanted organ failure.

Several processes have been identified in the host rejection of transplanted tissue. After transplantation of a donor organ, recipient dendritic cells (DCs) encounter “foreign” antigen from the donor tissue that appear to be dangerous to the host, and present small bits of its proteins, or peptides, to host B cells. These B cells then produce specific antibodies (Abs) that initiate other processes leading to the destruction of the foreign graft tissue. More often in graft rejection, however, the donor’s DCs present the donor’s own “self” peptides to host helper T cells, also called CD4 T cells, that have not yet encountered these foreign peptides. These CD4 T cells then may either help to establish cytotoxic (CD8) T cells that mount a T_H1-dominated response in attempt to destroy the dangerous cells, characterized by production of inflammatory cytokines, or the CD4 T cells may themselves mount a T_H2 immune response, typified by production of eosinophils, cells that secrete toxic granules that help counter foreign or potentially dangerous cells. Obviously, however, when a patient receives a transplanted tissue or organ, the survival of the transplanted tissue is critical for the success of the transplant, and thus these immune processes must be dampened to ensure that this occurs.

Typically, patients who undergo organ or tissue allotransplants are treated with immunosuppressants to prevent acute graft rejection. Corticosteroids are used most often to dampen the immune response and to counter the inflammation and consequent tissue damage that may occur, but they possess several severe side effects in addition to immunosuppression, and may lead to the recipient developing other infectious diseases as a result. Current therapeutic research is thus targeted at elucidating the molecular processes involved in graft rejection, which may ultimately yield treatments that can target specific molecular pathways without inducing such broad immunosuppressive effects. Just earlier this month, a study was published in The Journal of Immunology by Booth and colleagues that identifies a potential mechanism by which the host immune system induces cardiac graft rejection. The paper implicates a critical role for the cytokine IL-6 in graft infiltration by host lymphocytes (T cells and B cells) and the shaping of CD4 T cell response associated with CD4-dominant cardiac graft rejection. To achieve this, the authors utilized a mouse model in which they performed cardiac transplant and examined the role of IL-6 in either CD4- or CD8-dominated responses.