New Approaches in Immunotherapy

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Science  15 Jan 2010:
Vol. 327, Issue 5963, pp. 249
DOI: 10.1126/science.1186704

The past decade of research on the immune system has seen an incredible expansion of knowledge in the area of innate immunity. Analysis over the preceding years had focused largely on how T and B cells orchestrate immune responses to specific pathogens, and how their memory of these encounters confers long-lasting protection. In contrast to these specific “adaptive” mechanisms, innate immunity is driven by a plethora of proteins produced by a wide range of cells throughout the body, and it provides immediate broad-spectrum responses to foreign invaders. This new understanding of innate immunity is providing insights into host reactions to noninfectious diseases such as cancer, to antigen-independent inflammatory conditions such as periodic fever syndromes, and to the inflammatory modulation of basic cellular metabolic processes. As this special issue on innate immunity points out (p. 283), ongoing research to further characterize this complex response system has great potential for identifying new therapies to treat human disease.

Three major families of molecules function in innate recognition and are a focus of the special issue: the Toll-like receptors, the RIG-I–like receptors, and the Nod-like receptors. Most is known about the first two types, which have important roles in recognizing viral and bacterial components. The Nod-like receptor family—the largest and most diverse of the three—has many unresolved features. Much of the focus has been on this family's functional association with the inflammasome, a scaffold of proteins that triggers specific inflammation pathways and cell death. But there is growing evidence that this represents only one aspect of Nod-like receptor activity, and analyses of their actions in other inflammatory pathways will probably lead to important new insights.


A feature of all three molecular families is that, despite wide upstream divergences, multiple signals tend to converge on shared, downstream effector signaling pathways. To date, relatively little is known about how responses are nevertheless adjusted to appropriately match the diversity of upstream pathogen recognition events. Research on the regulation of pathways controlled by the RIG-I–like receptors has been promising in this respect. But an important goal, essential for the design of next-generation adjuvants, is to develop a thorough understanding of how all these innate immune signaling pathways are modulated to produce qualitatively different outputs in response to different types of threats. This knowledge is also likely to advance our understanding of immune dysregulation and hyperactivation, such as that producing the “cytokine storm” implicated in the deaths of individuals infected with the H5N1 influenza virus.

We now know that the first responders to pathogens are often the infected (or bystander) host epithelial and endothelial cells, rather than the arsenal of “professional” innate immune cells (macrophages and dendritic cells). These “nonimmune” host cells can potentially express members of all three innate recognition receptor families, and activation of the signaling pathways that they control results in the secretion of chemokines that recruit and activate the antimicrobial programs of adaptive responders. In parallel, nonimmune host cells alter key components of their own biology and metabolism to subvert and contain intracellular pathogens.

Detailing the relationship between innate immune recognition and host cell metabolism remains an important priority, as these physiological perturbations are likely to affect organ-level function. Thus, for example, although influenza infection may be cleared by the adaptive immune response or controlled by drugs, an individual may still succumb to severe lung damage, either as a direct consequence of viral insult or from the associated inflammatory response. Similarly, as we look more closely at the interplay between injured coronary tissue and the monocytes and macrophages that contribute to arterial plaque formation in cardiovascular disease, it becomes clear that expanding the scope of innate immunity research to include the entire diversity of cells in an organism is a major priority for molecular medicine.

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