Immunology: Highlights From A Hot Biological Field

Some of the most influential papers in 1992, according to data provided by the Philadelphia-based Institute for Scientific Information, were in immunology. This is not surprising, given the field's applications in stemming AIDS, cancer, and other pressing diseases. The most cited paper published within the last two years is from the Max Planck Institute for Biology in Tbingen, Germany (K. Falk, et al., Nature, 351:290, 1991). This paper, which by the end of February 1993 had been referred to in 220 subsequent articles, deals with an advance in the understanding of MHC, the major histocompatibility complex molecules. MHC binds short peptides that are derived from intracellular proteins. The peptides are then presented to the cell surface for inspection by the immune system. Native proteins produce "self peptides," which are recognized as friendly, while foreign proteins give rise to antigenic peptides and stimulate an immune response. In the work by Kirsten Falk and associates, the breakthrough was in the characterization of peptides that are bound to MHC molecules. As the authors point out, knowledge of the peptide motifs of individual MHC molecules can "help with synthetic or recombinant vaccine development and potentially also for intervention in autoimmune diseases or graft rejection." A paper from the labs of Don Wiley, a professor of biochemistry and biophysics at Harvard University (T.S. Jardetzky, et al., Nature, 353:326, 1991), appearing a few months after the Max Planck findings were published, has been cited in close to 85 papers as of February 1993. This article pushed the knowledge of these peptides still further. Ted Jardetzky, the paper's first author, told The Scientist that for this study, the researchers worked with a type of MHC molecule called human leukocyte antigen (HLA). "We isolated HLA from the surface of cells, denatured it, and collected a pool of small molecular- weight peptides. Falk and colleagues had just demonstrated that similar peptide pools contain sequence motifs which differed between HLA molecules. We were able to fractionate this complex pool of peptides--more than 100 to 1,000 different peptides--and sequence 11 `self peptides.' Seven of these peptides matched to sequences from known proteins, providing a definitive demonstration that normal intracellular proteins are also being transported to the cell surface for immune surveillance. These complexes of self peptide and HLA can have both good and bad consequences. In the case of autoimmune diseases, some T cells react inappropriately against self, but for some tumors, the expression of self peptides could be the key to an immunological cure." Work that has pointed the way to understanding how immunosuppressive drugs work, coming out of the laboratories of Harvard University chemist Stuart Schreiber and Gerald Crabtree at the Beckman Center for Molecular and Genetic Medicine at Stanford University, has been a citation-rich region of immunology. Michael Flanagan, who was a postdoc in Crabtree's lab and is currently working at Gilead Sciences in Foster City, Calif., says he is not surprised that the work has attracted attention. "Everything was done to maximize exposure," he says. His group's paper, "Nuclear association of a T-cell transcription factor blocked by FK506 and cyclosporin A" (W.M. Flanagan, et al., Nature, 352:803, 1991), was promoted in the "News and Views" section of the same issue of Nature in which the paper appeared (A.L. DeFranco, page 754). Meanwhile, an issue of Cell published the previous week contained not only Schreiber's paper, "Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes" (J. Liu, et al., Cell, 66:807, 1991), but also an accompanying mini-review, "When worlds collide--Immunosuppressants meet protein phosphatases" (F. McKeon, page 823). In the Crabtree paper, which has attracted about 100 citations since publication, the researchers demonstrated that a genetic transcription factor, NF-AT, which is critical to T-cell gene activation, is apparently a specific target of the immunosuppressants. Schreiber's paper, which has racked up an impressive 163 citations since publication, identified a different mode of action of immunosuppressive drugs. That is, they block the phosphatase calcineurin, which forms an essential link in the signaling pathway that activates T cells. Just prior to this report, Schreiber surveyed progress in the study of immunosuppressants in "Chemistry and biology of the immunophilins and their immunosuppressive ligands," an article that has been cited a total of 185 times since its publication (S.L. Schreiber, Science, 251:283, 1991). According to Schreiber, immunosuppressants like cyclosporin A and FK506 act early on in the signal transduction cascade that leads to T lymphocyte activation, while other compounds apparently interfere with other steps in the signal pathway. So, the work with immunosuppressants transcends the field of immunology, giving insight into the molecular biology of signal transduction. As Schreiber wrote in the Science paper: "The research outlined in this article illustrates an approach to the study of cellular, particularly cytoplasmic, phenomena. In this approach, modern techniques in chemistry and biology are melded so that the interactions of natural and synthetic ligands with their cellular receptors can be explored. Small molecules are used as probes, first for identification and isolation of relevant proteins in a system of interest and then for the development of a detailed understanding of the system through studies of structure and function. Such a chain of events has been initiated by a family of immunosuppressants, and other natural products might be useful as probes for a diverse set of events that includes protein trafficking and cytoskeletal dynamics. Although there is still much to be learned about cytoplasmic signalling mechanisms with use of immunophilin and immunosuppressive probes, the prospects for insights appear promising." Many of the other highly cited papers in immunology also deal with signal transduction. Joseph Bolen, who is a research scientist at the Bristol-Myers Squibb Pharmaceutical Research Institute in Princeton, N.J., was a coauthor of a 1991 paper appearing in the Proceedings of the National Academy of Sciences (A.L. Burkhardt, et al., 88:7410, 1991) that has been cited in more than 65 papers. Speaking of this paper, "Anti- immunolglobulin stimulation of B lymphocytes activates src- related protein-tyrosine kinases," Bolen told The Scientist: "Only in recent years has it been appreciated that enzymes possessing tyrosine kinase activity, originally noted as the oncogenes of retroviruses, are involved in normal cell signal transduction. These facts, coupled with the significant progress made by immunologists in the identification and characterization of receptors on cells of the immune system, has led to the close scrutiny of the potential role of tyrosine protein kinases in signal transduction by hemopoietic cell-surface molecules. Among receptors of this class, much attention has been focused on the surface immunoglobulin (or antigen receptor) of B cells. "This particular paper simply demonstrates that at least three different closely related tyrosine protein kinases of the src family--the blk, lyn, and fyn gene products--can be enzymatically activated when B cell-surface immunoglobulins are crosslinked, which is a laboratory means to mimic antigen binding. "Several tyrosine protein kinases appear to be responsive to the surface engagement of the B cell antigen receptor," Bolen said. "These observations provide a starting point to determine the role of the individual kinases in B cell signal transduction." Also among the high-impact papers are those involving adhesion receptors--cell-surface molecules that regulate the migration of lymphocytes and the interactions of activated cells during immune reponses. Probably the hottest review paper in this field, "Adhesion receptors of the immune system," appeared in Nature in 1990 and since then has racked up an astounding 892 citations (T.A. Springer, 346:425, 1990). As Timothy Springer, a professor of pathology at Harvard University, writes in this paper: "There are important interactions between antigen receptors and receptor molecules involving signaling pathways and interactions with gene expression. Further studies on three-dimensional structure and interactions with signaling pathways and the cytoskeleton promise to provide exciting insights into the mechanism of function of adhesion receptors. The role of these molecules in vivo in guiding cell interactions and localization in the complex microarchitecture of lymphoid organs, as well as in immune responses in other tissues, is another area that promises to yield rich insights." An adhesion-minded review from Martin Helmer of the Dana-Farber Cancer Institute in Boston has developed its own devoted following with more than 370 citing papers to date (M.E. Helmer, "VLA proteins in the integrin family: Structures, functions and their role in leukocytes," Annual Review of Immunology, 8:365, 1990). Helmer told Science Watch, a newsletter published by the Institute for Scientific Information (April 1992, page 5): "There's widespread interest in the integrin family because essentially all cells and all tissue types, with the exception of red blood cells, use different members of this family for various adhesion processes. "Basic researchers in developmental and cell biology, cancer, and immunology--they all have a stake in learning how and why cells adhere. These molecules are on T cells, B cells, and monocyte cells of the immune system," Helmer said. "People are now looking at these molecules as more than just Velcro strips lining the outside of a cell and providing adhesiveness. The next step is to find out how these molecules translate that information into cellular signals. They're now viewed as true receptors, in that they bind and then important events follow, involving gene induction, morphology, migrations, and spreading. Depending on which members of the family have contact, you get a whole host of subsequent events. It's an area of research that's really attracting a lot of attention." And not to be forgotten, of course, are the hot papers reporting original research on cell adhesion, with the following racking up exceptional citation records: 220 citations: M.L. Phillips, et al., "ELAM-1 mediates cell adhesion by recognition of a carbohydrate ligand, Sialyl-Lex," Science, 250, 1130, 1990. 172 citations: G. Walz, et al., "Recognition by ELAM-1 of the Sialyl-Lex determinant on myeloid and tumor cells," Science, 250:1132, 1990. 164 citations: J.B. Lowe, et al., "ELAM-1 dependent cell adhesion to vascular endothelium determined by a transfected human fucosyltrans-ferase cDNA," Cell, 63:475, 1990. 100 citations: Y. Shimizu, et al., "Activation-independent binding of human memory T cells to adhesion molecule ELAM- 1," Nature, 349:799, 1991. 59 citations: E.L. Berg, "A carbohydrate domain common to both Sialyl Lea and Sialyl Lex is recognized by the endothelial cell leukocyte adhesion molecule ELAM-1," Journal of Biological Chemistry, 266:14869, 1991. 56 citations: F.W. Luscinskas, et al., "Cytokine-activated human endothelial monolayers support enhanced neutrophil transmigration via a mechanism involving both endothelial- leukocyte adhesion molecule-1 and intercellular adhesion molecule-1," Journal of Immunology, 146:1617, 1991.

Immunology: Highlights From A Hot Biological Field

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