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Chapter 43 : Laboratory Monitoring of Cytokine Therapy
The goal of laboratory monitoring for cytokine therapies is to maximize the efficacy and minimize adverse effects of these agents. The optimal monitoring strategy will depend on the characteristics of the specifics of the therapy, but general strategies can be identified. In IFN-β therapy for multiple sclerosis (MS), many of these general strategies have been utilized with significant benefit to MS patients. In other cytokine based therapies (CBTs), monitoring has not been as extensively utilized. There are two major types of laboratory measures used to monitor CBTs: biomarkers of disease and cytokine-induced molecules. Binding-antibody (BAb) assays are generally faster, more sensitive, and more inexpensive than other assays. Enzyme-linked immunosorbent assay (ELISA) technology can be used, which allows for the screening of hundreds of samples in a few hours in an automated fashion. CBTs are a subclass of biologicals that have profound biological effects, many of which are poorly understood. These drugs are recent additions to therapy, and consequently, we are still relatively early in a growth curve about their optimal use. Monitoring of their effects is going to be important for many reasons. One of the major reasons is that these therapies tend to be highly immunogenic and the optimal approach for identification of antidrug antibodies and their potential to neutralize drug effects needs to be identified. Another reason is the high cost of these biologicals, which makes optimal use critical.
Diagram of cellular effects of IFN-β as a prototype of a CBT. The cellular response to IFN-β is a prototype system in which receptor binding by the cytokine results in upregulation of a host of early, intermediate, and late genes, with complex downstream effects.
Histograms of gene expression of MxA (GEM) in controls without IFN-β injection (top) and MS patients 12 h after IFN-β injection (bottom). The x axis represents log2 of normalization ratios, i.e., 2 to the power (ΔΔCt) where ΔΔCt is (Ct of MxA - Ct of GAPDH) for sample minus (Ct of MxA - Ct of GAPDH) for normal control. The y axis represents number of patients. The expected response after injection is a strong increase in level of MxA mRNA as detected by real-time reverse transcription-PCR. In this group of patients the MS patients had a mean of over 16-fold increase in MxA mRNA after injection.
Stages of ADB in IFN-β-treated MS patients. Four stages can be identified in the interplay between antibody and bioactivity of IFN-β as measured by the GEM assay. ♦, Nab level (%); ▀, bioactivity (%). The y axis represents percent maximal response, and the x axis represents months post initiation of therapy.
Partial list of cytokines available for therapy in the autumn of 2004