Genomic and Proteomic Analysis of Immune Tolerance

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Historically, the assessment of graft function, presence of autoimmune-related pathology and analysis of circulating immune cell components and function, the latter through quantification of serum proteins (such as allo- and autoAbs, complement or cytokines), have been used as biomarkers to assess the level of immune responses related to tolerance and immunity. However, earlier and more informative indicators and prognosticators of the pathological or tolerant states in graft rejection and autoimmunity are now being sought via proteomic approaches, such as protein arrays, surface-enhanced laser desorption ionization/time-of-flight mass spectrometry, and two-dimensional gel electrophoresis combined with mass spectrometry (110,111). Although these technologies are in their infancy with regards to applications in immunological systems, they have potential, in the long-term, for greater sensitivity and provision of information than is currently available using enzyme immunoassay and other clinical or laboratory measures.

Likewise, microarray analysis continues to evolve as a broadly applicable and powerful method to identify candidate genes, expression levels of which are altered during diverse biological processes. Recent studies have aimed, through array analysis, to dissect the processes underlying allograft changes during surgery and transplant rejection or acceptance (112-114), as well as in organ-specific autoimmune responses (115). Furthermore, the central importance of DCs to tolerance regulation has lead to focused examination of their gene regulation following exposure to tolerogenic (e.g., IL-10, vitamin D3) (116,117) or inflammatory stimuli (e.g., TLR ligands) (118). Similarly, peripheral blood mononuclear cells possess global patterns of gene expression dictated by their exposure to immunomodulatory cytokines and other factors, and as such, the resultant molecular signature of these cells may disclose the condition of the body. Bennett et al. (119) demonstrated the power of microarray analysis of peripheral blood mononuclear cells when they confirmed the role of IFN-y in the pathogenesis of systemic lupus erythematosus, based on a pattern of upregulated IFN-induced genes, which was lost upon successful steroid treatment of the disease. These array data also established a possible role for immature granulocytes in systemic lupus erythematosus (119). As these data clearly indicate, informative gene expression patterns are contained in the circulating leukocyte population. As continued, focused analysis of DC, T-, and B-cell populations in various tolerant or reactive states of transplant, cancer, and autoimmunity are completed, a more precise and comprehensive picture of the immune vs tolerant state will emerge.

As these phenotypic, genomic, and proteomic analytic and diagnostic tools continue to evolve and become standardized, their use as (potentially powerful) clinical tools to rapidly and broadly assess patterns of immune reactivity or tolerance, and their utilization to distinguish patients who may be "predisposed" to tolerance, or require immunosuppressive therapy, can be envisaged. Similarly, their value in rapid, real-time assessment of the impact of novel therapeutic strategies aimed at modifying the immune response to self, tumor-associated or alloAgs, is likely to be realized.

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