BioWorld International Correspondent

LONDON - Scientists have discovered a new way in which cells process antigens, with riveting implications for cell biology. The novel process - in which antigen fragments are spliced and reversed - hugely increases the number of peptides that can be made from a single protein.

The researchers who carried out the work suggest that there could be an "entire universe" of alternative antigenic peptides in existence, many of them with roles in the immune response to tumors or pathogens.

Benoit Van den Eynde, professor of immunology at the Catholic University of Louvain in Brussels, Belgium, and researcher at the Brussels branch of the Ludwig Institute for Cancer Research, told BioWorld International: "Scientists will be keen to know what this means for the development of new cancer vaccines. If many more antigenic peptides are available - and our study suggests that they are - then this could have enormous implications for new vaccines and immunotherapies."

The study, a collaboration between researchers in Belgium and at the Fred Hutchinson Cancer Research Center in Seattle, is published in the Sept. 8, 2006, issue of Science. Its title: "An antigen produced by splicing of non-contiguous peptides in the reverse order."

When a cell needs to dispose of a protein, it chops it up and displays the fragments (or peptides) on its surface. The process is known as antigen processing. Once on the surface, the peptides are available to cytotoxic cells that will recognize foreign antigens or those from viruses or tumors, and those can trigger an immune response directed at the foreign tissue, virus or tumor.

Van den Eynde and colleagues, together with collaborators led by Edus Warren of the Fred Hutchinson Cancer Research Center, now have shown that antigen processing can involve turning peptides back to front before sticking them together again.

Van den Eynde said: "It is important to realize that this is the first time anyone has identified a biological product - a protein encoded by a gene - that does not respect the colinearity dogma that says amino acids must appear in a protein in the order in which they are encoded in the DNA."

The discovery came about because the two groups were attempting to identify which peptide on a cancer patient's cells had stimulated the production of cytotoxic T lymphocytes. Ultimately, if such a peptide could be identified, it could be used to stimulate the immune system to produce such cells, which would attack the cancer.

In this particular patient, the cytotoxic T lymphocytes had developed following treatment for myeloma, a cancer of the blood cells. The patient had received whole-body irradiation to eliminate her own bone marrow, followed by a hematopoietic stem cell transplant from a related donor.

Although the donor and the recipient were a good match, cells in the donated tissue started to reject the cells of the host. This is a condition known as graft-vs.-host disease (GVHD).

Although GVHD can cause problems, it also can be helpful to the patient: Those who develop it have a lower risk of relapse. The reason is that the cells of the transplant that attack the host's tissues also attack any cancer cells remaining in the body. That's called the graft-vs.-leukemia response.

In this case, the GVHD was quite mild, but Warren wanted to find out which antigen had stimulated the development of the attacking cytotoxic T lymphocytes.

Van den Eynde explained: "This would be useful if the genes involved were expressed exclusively in the hematopoietic system. If we could find such antigens, we could vaccinate the patient after the graft, in order to induce the graft-vs.-leukemia response but without damaging other body tissues."

Van den Eynde's lab is skilled in identifying antigenic peptides recognized by cytotoxic T lymphocytes, so Warren arranged to spend a year there working with him. They identified the gene easily, but the peptide itself eluded them.

Having pinpointed two antigen fragments that they found were required to stimulate the cytotoxic T cells, they even tried splicing them together to see if that would work, but it didn't.

"Then, just a few days before Edus was due to go back to Seattle," Van den Eynde said, "we were discussing the results for the last time, and one of us had the idea that perhaps we needed to invert these two important fragments. So we tested it, and we found that the inverted peptide was nicely recognized by this patient's cytotoxic T cells."

Unfortunately, the peptide turned out to be encoded by a gene that was not exclusively expressed in the hematopoietic system. "This means that it is not the best candidate for therapy after bone marrow transplantation, but there are other candidates that people are starting to use for this purpose," Van den Eynde said.

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