Additional Reading Summary, Week 7

Sorry for the late post. There were so many articles that it took a little longer than expected. Here is my summary of the articles.

“The T-lymphocyte antigen receptor—paradigm lost”
Jens Jensenius and Alan Williams

This article speaks about the ongoing paradigm shift from the idea T-cells were essentially the same as membrane bound antibodies. It was thought for quite some time that if the T-cell receptor was so similar to the immunoglobulin, identifying structures with V-domains on T-lymphocytes would allow scientists to identify the receptor. The article talks about why this paradigm should be shifted due to the disparity between immunoglobulin and the T-cell receptor. For example, the T-cell receptor is unable to directly bind unprocessed antigen. In addition, the receptor’s co-recognition of the histocompatibility complex along with foreign antigen indicates the necessity for the paradigm shift away from a foundation on immunoglobulin.


“On the Trail of the T-cell Receptor”
Mark Davis

Dr. Davis provides a great summary of the work that he and his lab did to be the first to clone the T-cell receptor. He gives a brief history of T-cells and the many theories that were proposed in regards to the receptor, such as the two receptor model, in which one receptor recognized antigen and the other the MHC. Dr. Davis recounts his decision to work on the T-cell receptor, a looming unknown in immunology, by applying what he knew best from CalTech, Cot curves and subtractive hybridization. Luckily, he determined that there was only a 2% difference between the B-cells and T-cells (approximately 100-200 genes). Therefore, using a library of cDNA probes to screen the B and T-cell libraries, the gene was finally narrowed down using the last clone, TM-86. Dr. Davis then moved to Stanford from the NIH to continue the research, and the process kicked into full gear. Once he presented the results at an immunology conference in Tokyo, the subject exploded, with countless other researchers desperately working to find the other chains of the receptor. Ultimately, Dr. Davis gives gave a great personal review of the process that went into discovering the T-cell receptor and the “breaching a major bottleneck in the understanding of the mechanism of the T-cell.”


“Isolation of cDNA clones encoding T cell-specific membrane-associated proteins”
Mark Davis, et al.
“Sequence relationships between putative T-cell receptor polypeptides and immunoglobulins”
Mark Davis, et al.


These two articles summarize the findings of Dr. Davis and his lab in more detail. The first article entitled, “Isolation of cDNA…” was the first paper to hint that the T-cell receptor gene had been found. Dr. Davis and his lab had determined that one of the cloned DNA copies of mRNA expressed only in T-cells, which was also a membrane bound protein, also hybridized in a region of the genome known to rearrange in T-cell lymphomas and hybridomas. These factors all indicated that this gene did in fact code for the surface T-cell receptor.

The second article recounts the comparison of this T-cell specific cDNA with cross-reacting cDNA clones from a thymocyte library. Their subsequent reactivity indicated that a variable, constant, and joining region were present within the gene segment and were very similar to those segments found in immunoglobulin proteins. Somatic rearrangement had already been observed, and further supported that this isolated gene segment encoded one of the chains of the T-cell receptor.

HIV Vaccine Research a Field Apart From Classic Vaccinology

http://www.medscape.com/viewarticle/721410

Bob Roehr

The research on HIV vaccinations has decided to break away from claissic vaccinology and the adaptive immune reponse and carve a path of its own. The major shift is that instead of looking for ways to protect against infection and instead focus on finding ways to change the nature of the infection. The reason? The classical approaches that have been successful in the past simply do not apply to HIV. Researchers have found that many attempts to use the same techniques have been unsuccessful.

The changing face of research boils down to looking at an immune response that protects against acquisition, which is very different from the immune response that actually controls chronic virus replication.

The molecular pathway that makes this the case is hypoglycosylate. Hypoglycosylate appears to be easier to neutralize than variants found later in infection. Once the virus has takenn a hold in the body, the virus rapidly diverges and diversifies with conformational changes and the addition of glycands that can shield antibody binding sites, and the virus prevails. Once the virus robustly replicates and gets into the lymphoid tissue a chance for a vaccine to be effective is over. Now, there is no chance to eradicate the virus s the focus really needs to be on blocking acquisition.

Mark Davis: On the Trail of T-Cell Receptors

In less than 10 pages, Mark Davis provides an account of his landmark discovery of the nature of the T-cell receptor.

By nature, T-cells can recognize a number of foreign objects through cooperation with the MHC, or Major Histocompatability Complex. The mechanism behind their partnership earlier in the century was unknown. Davis decided to approach the issue by finding a way to clone interesting lymphocyte genes quickly by essentially hybridizing cDNA between cell types and "subtracting" out common genes, leaving only the unique ones for analysis. By analyzing differences between both T and B cells, Davis found a series of genes that could elucidate the variable regions of the T cell and how they are able to recognize so many different pathogens.

After a whirlwind of events coming down to his last clone, Davis found a region that seemed like a classic rearranging gene. With the help of enthusiastic Japanese scientists, the alpha, beta, gamma, and delta chains were identified, completing the set of four T-Cell receptors we have become familiar with today. Today's consensus model has one receptor, where the binding site is ultimately designed to recognize both the antigen and the MHC.

Daniel

A Clamp for Emerging Flu Viruses: Researchers Unravel Secret of Innate Immune Response

Website: http://www.sciencedaily.com/releases/2010/04/100428085843.htm

Article: Albert-Ludwigs-Universität Freiburg. "A Clamp for Emerging Flu Viruses: Researchers Unravel Secret of Innate Immune Response."ScienceDaily 30 April 2010. 9 May 2010 /releases/2010/04/100428085843.htm>.

Researchers have just unraveled the structure and mechanism by which the protein, Mx (short for myxovirus resistance) protects the body from influenza. Previous to this discovery, the exact mechanism by which this protein protected was unknown. It is now understood that Mx works like a molecular machine by joining individual molecules into a macromolecule shaped like a ring. It is only once it has achieved this right structure that it is fully activated. The stalk is the element in Mx that is responsible for the forming of the ring and has been the center of research for many years.

It is now understood that the Stalk functions as a clamp to deactivate and restrain the virus in infected cells. New pandemics can only arise when pathogens are especially powerful and harmful. Understanding the basis of Mx at the molecular level, not just the atomic level, will play a huge role in upcoming drug and antiretroviral development in the coming years.

Dr. McDevitt Intro

He sort of jumped right into his lecture before I got the chance to give this introduction, which is sort of a pity because he's a really interesting guy. Here it is for those who are interested:


Dr. Hugh McDevitt has had a very distinguished career. He began with getting his BA degree in biology at Stanford in 1952, graduating with honors. Three years later he received his MD degree from Harvard. He interned at Peter Brent Brigham Hospital in Boston followed by residency at Bellevue Hospital in New York. He then spent two years in Japan with the US Army as a Captain in the Medical Corps before returning to a postdoc position at Harvard and then completing his residency at Brigham. He spent some time as a Special Fellow at the National Institute for Medical Research in London before returning to Harvard to become an instructor in 1964, the same year my mentor, PJ Utz, was born.

In 1966 Dr. McDevitt became a professor at Stanford in the department of medicine. From 1970 to 1976 he was the Chief of the division of immunology, and at about roughly the same time was also director of the clinical immunology laboratory. From 1986 to 1990, he was the chairman of the department of microbiology and immunology at the Stanford med school, and from1988 to 2001 he was a Burt and Marion Avery Professor of Immunology (endowed).

He is the recipient of numerous honors and awards. Just to name a few of the more prestigious ones, he was admitted to the National Academy of Sciences in 1977 and the Institute of Medicine in 1983. In 1984 he received the American College of Physicians Award for Research in Medical Sciences and the American Academy of Arts and Science. In 1986 he was awarded the Lee C Howley, Sr. Prize for Research in Arthritis. A year later in 1987 he was awarded the Paul Erlich Prize. In 1995 he was elected to the Royal Society in London. I could keep going, but then we wouldn’t have time to actually hear him speak.

Some other interesting facts: Dr. McDevitt and his wife just recently returned from Italy where they got to see the treausures of Firenze and the ruins of Leopard’s houses in Sicily. One of his best friend’s is Lorenzo di Medici at the National Gallery in Washington. He also is a huge dog lover and has a 3 year old Labrador named Pippi.

Reading Summary, Week 6

HLA-DQ gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus

John A. Todd, John I. Bell, & Hugh McDevitt

In studying polygenic human diseases, specifically autoimmune disease, research has found a higher frequency of lymphoid cell-surface proteins encoded in the HLA-D regions of the MHC (class II antigens). These HLA class II antigens are expressed on the surface of B cells and antigen-presenting cells; interaction with the T-cell receptor, antigenic peptide, and the class II molecule then leads to an immune response to the antigen. From this, we learn that the immune responsive in part determined by polymorphic amino acids present in the class II molecules.

Type I Diabetes is the result of the destruction of insulin producing islet cells of the pancreas, and some have argued that this disease develops from an autoimmune response to an islet antigen and is mediated by T-cells. It is estimated that the HLA-D region contributes over 50% of the heritability of this polygenic disease.

This study sequenced polymorphic class II gene products from three patients with Type I diabetes against several control patients.

The major findings of the article were that there were no unique class II sequences found only in the Type I diabetic patients, that the DQ-B-chain amino-acid sequence is correlated with predisposition to Type I diabetes, and that this susceptibility is largely dependent on amino-acid residues (position 57). The authors argue that DQ-B allelic polymorphisms at position 57 determine the specificity and extent of the autoimmune response against the islet cell antigens (with T cell help or suppression).

Provenge: the Next Rituxan

This past Thursday, the FDA approved Dendreon Corp.’s new prostate cancer therapeutic, Provenge. Dendreon is a Seattle based biotech that has been trying to get approval for Provenge since late 2006, but the FDA requested additional data. Provenge is the first of an entirely new class of cancer therapies that works by stimulating the immune system to attack the disease. The vaccine is an ex vivo-loaded dendritic cell augmented with the treatment of GM-CSF fusion protein.

Provenge’s approval is a historic development in the fight against cancer and will hopefully pave the way for similar active immunotherapies. The immunotherapy of cancer has been traditionally confined to passive immunotherapy, a field that revolves entirely around the monoclonal antibody. Ronald Levy (here at Stanford) was the first to use monoclonal antibodies to induce remission in patients with B-cell lymphoma, which lead to the FDA’s approval of rituximab (Rituxan) in 1997 as a cancer therapeutic. Rituxan ushered in a new era for biologic drugs, and within 5 year of its approval, 5 more monoclonal antibodies were approved in the U.S.

To highlight the gravity of the current approval, many have directly compared the approval of Provenge to the approval of Rituxan. Several other companies including Celldex and GlaxoSmithKline are currently developing other active immunotherapies, and Provenge’s approval suggests that these therapeutics could also make it to market and stimulate a new interest from pharmaceutical companies and venture capitalists.

Provenge is proof that active immunotherapy works, but we will have to wait and see if this method of treatment takes hold.

Sources:

Cha, E., Fong, L. “Therapeutic for Prostate Cancer.” Curr Opin Mol Ther 12, 77-85 (2010).

http://online.wsj.com/article/BT-CO-20100430-716345.html?mod=WSJ_latestheadlines