Antibodies turn stem cells into immune cells

LA JOLLA Richard A. Lerner made his scientific reputation by unraveling novel characteristics and uses of antibodies, helping invent new tools in the process. Upon stepping down as president of The Scripps Research Institute at the beginning of 2012, Lerner didn't walk out the building with a golden test tube or petri dish. The self-proclaimed lab rat continued his work on his great scientific love, and has contributed to a remarkable series of papers of antibodies establishing their virtuosity in various cellular processes.

Among the Lerner team's findings this year alone: Antibodies can convert bone marrow stem cells directly into neural progenitor cells; and they can mimic the effects of different chemicals such as the blood-clotting hormone thrombopoietin, or TPO.

The latest finding, published in the Proceedings of the National Academy of Sciences, is that antibodies can convert stem cells into dendritic cells. These dendritic cells are immune system cells process fragments of protein that aren't part of the body and present them to other immune cells, so they recognize it as foreign.

The paper was published on Aug. 26, two days before Lerner's 75th birthday. Lerner was senior author on this paper, as he was on the first two. Kyungmoo Yea of the Scripps Korea Antibody Institute was first author.

Antibodies are best known for their infection-fighting role -- the body makes them in astronomical configurations, some of which by chance will bind to a molecular target. Lerner's work demonstrates that this conception grossly underestimates the versatility of antibodies.

Earlier in his career, Lerner helped develop methods of generating large libraries of antibodies, which could then be screened for utility. His work led to the discovery of Humira, which treats autoimmune diseases such as rheumatoid arthritis.

Humira blocks TNF from binding to receptors, thus inhibiting inflammation associated with some autoimmune diseases. But antibodies are more than just antagonists that block receptor activity, they are also agonists that turn on receptors. That's what the paper about the TPO agonist showed.

In the new paper, Lerner, Yea and colleagues extend this principle to describe a method for finding antibodies that act ac agonists to control stem cell fate, or what mature form a stem cell will ultimately take. The team inserted "libraries" of antibody genes into TF-1 erythroblasts using lentiviruses, which incorporate their genes into the genome of the host cell. The cells then express the antibody genes, and produce a range of antibodies, which have varied effects on the cells.

As the paper described the method, "each cell becomes a selection system unto itself." As for what to select, in this study, it was shape.

These cells were grown in colonies in soft agar, and their structures observed. Those with interesting shapes different from control cells were examined, and their antibody genes extracted. They then chose three antibodies for further study because they came from colonies with the most interesting shapes. The choice was arbitrary.

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Antibodies turn stem cells into immune cells