In order for white blood cells to perform their protective functions, they must migrate to specific anatomic locations. This is true not only for the immediate response to pathogens i.e., scavenging leukocytes migrate to sites where the body's defenses have been breached, but also for mounting an effective immune response. For example, antigen presenting cells and T lymphocytes must accumulate in the same subanatomic locales in secondary lymphoid organs to increase the probability that they will come into physical contact. We now know that most leukocyte trafficking is controlled by low molecular weight, secreted chemotactic proteins called chemokines. Over 40 human chemokines have been identified, and they all exert their chemoattractant effects by activating members of the 7-transmembrane-spanning, G protein-coupled family of receptors.

Our interests in chemokine biology run the gamut from understanding the molecular basis of chemokine action to the function of these proteins in disease, and our approaches are similarly broad based, including basic biochemistry and the development of genetically modified animal models. Our early strategy was to focus on one chemokine in depth, namely monocyte chemoattractant protein-1 (MCP-1) now called CCL2 in the new systematic nomenclature. Our biochemical analyses demonstrated some of the structural requirements for MCP-1 activity and led to the discovery of a potent antagonist which is now in commercial development for clinical use. We have also developed an MCP-1-deficient mouse which has helped us to demonstrate MCP-1's essential contributions to diseases such as atherosclerosis and multiple sclerosis. We also use MCP-1 to explore ways in which the chemokine system modulates T helper cell responses.

More recently, we have begun to focus on the role of chemokines in cancer. Cancer cells secrete many chemokines, including MCP-1 in some cases, but their function in this context is unclear. We have shown that high concentrations of MCP-1 in animal models can stimulate rejection of a tumor xenograft, but this would hardly be the reason underlying tumor cell secretion of these proteins. Instead, we and others think that tumor cells attract host leukocytes to provide growth and angiogenic factors that stimulate cancer progression. We are currently developing several endogenous cancer models to test this idea.

Selected publications:

• Rollins BJ, Sunday ME. Suppression of tumor formation in vivo by expression of the JE gene in malignant cells. Mol Cell Biol 1991; 11: 3125-31.


• Ernst CA, Zhang YJ, Hancock PR, Rutledge BJ, Corless CL, Rollins BJ. Biochemical and biological characterization of murine MCP-1: Identification of two functional domains. J Immunol 1994; 152: 3541-9.


• Zhang YJ, Rutledge BJ, Rollins BJ. Structure/activity analysis of human monocyte chemoattractant protein-1 (MCP-1) by mutagenesis: Identification of a mutant protein that inhibits MCP-1-mediated monocyte chemotaxis. J Biol Chem 1994; 269: 15918-24.


• Zhang Y, Rollins BJ. A dominant negative inhibitor indicates that monocyte chemoattractant protein 1 functions as a dimer. Mol Cell Biol 1995; 15: 4851-5.


• Rutledge BJ, Rayburn H, Rosenberg R, North RJ, Gladue RP, Corless CL, Rollins BJ. High level MCP-1 expression in transgenic mice increases their susceptibility to intracellular pathogens. J Immunol 1995, 155: 4838-43.


• Grewal IS, Rutledge BJ, Fiorillo JA, Gu L, Gladue RP, Flavell RA, Rollins BJ. Transgenic monocyte chemoattractant protein-1 (MCP-1) in pancreatic islets produces monocyte-rich insulitis without diabetes: abrogation by a second transgene expressing systemic MCP-1. J Immunol 1997; 159:401-8.


• Lu B, Rutledge BJ, Gu L, Fiorillo J, Lukacs NW, Kunkel SL, North, R Gerard C, Rollins BJ. Abnormalities in monocyte recruitment and cytokine expression in MCP-1-deficient mice. J Exp Med 1998; 187:601-8.


• Gu L, Okada Y, Clinton SK, Gerard C, Sukhova GK, Libby P, Rollins BJ. Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein-deficient mice. Mol Cell 1998; 2:275-81.


• Gu L, Tseng S, Horner RM, Tam C, Loda M, Rollins BJ. Control of Th2 polarization by the chemokine, monocyte chemoattractant protein-1. Nature 2000; 404:407-11.


• Huang D, Wang J, Kivisakk P, Rollins BJ, Ransohoff RM. Absence of monocyte chemoattractant protein 1 in mice leads to decreased local macrophage recruitment and antigen-specific T helper cell type 1 immune response in experimental autoimmune encephalomyelitis. J Exp Med 2001; 193:713-26.


• Soejima K, Rollins BJ. A functional IP-10/CXCL10-specific receptor expressed by epithelial and endothelial cells which is neither CXCR3 nor glycosaminoglycan. J Immunol 2001; 167:6576-82.
• Ren S, Rollins BJ. Cyclin C/Cdk3 promotes Rb-dependant G0 exit. Cell 2004; 239-51
  

Reviews:

• Gerard C, Rollins BJ. Chemokines and Disease. Nature Immunol. 2001; 2:108-15.


• Conti I, Dube C, Rollins BJ. Chemokine-based pathogenetic mechanisms in cancer. In: Cancer and Inflammation (Novartis Found Symp 256). Chichester: Wiley, in press.

Books:

• Rollins BJ, ed. Chemokines and Cancer. Totowa, NJ: Humana Press; 1999.

Barrett J Rollins, MD, PhD, Department of Medical Oncology, Dana-Farber Cancer Institute, Barrett J Rollins, MD, PhD, Department of Medical Oncology, Dana-Farber Cancer Institute, Barrett J Rollins, MD, PhD, Department of Medical Oncology, Dana-Farber Cancer Institute