Designer Antibodies: Cell Repair Mechanism Promises Immune System Control

Immunologists know there is genetic machinery that generates countlesskinds of antibodies in immature B cells developing in the bone marrow, but up tonow, they believed the design process was random and independent of antigen'spresence or influence. And they thought that once B cells matured, they losttheir ability to recombine their genetic material and produce new and differentantibodies.

Not so, says Dr. Garnett Kelsoe, professor of microbiology andimmunology at the University of Maryland School of Medicine. Mature B cells canreactivate the molecular machinery that makes new genes, which in turn designnovel antibody molecules. What's more, they can do it outside the bone marrow,in peripheral lymphoid tissues such as the spleen and lymph nodes. Even more significant is the fact that their renewed recombination of the Bcells' genetic material is antigen-driven. "The antigen in effect instructsfailing B cell to make a new, antigen-specific receptor," Kelsoe said. In otherwords, the intruder itself hands the defending army a blueprint for repairingineffective weapons against it.

"At least in theory, this means we could expand lymphocyte repertoires to meet apatient's needs," he said. For example, it should be possible to reconstitutemore quickly the damaged immune system of a cancer patient whose bone marrow hasbeen irradiated.

Kelsoe and colleagues report on their findings in the October 10 issueof the journal Science.

The University of Maryland School of Medicine researchers, includingKelsoe, Shuhua Han, Biao Zheng, and Michiko Shimoda, and collaborators Stacey R.Dillon and Mark S. Schlissel at Johns Hopkins University School of Medicine,immunized mice with antigen, jumpstarting an immune reaction. Lymphocytes beganproliferating in the spleen, growing into collections of active B and T cellsknown as germinal centers. In the germinal centers, where rapid mutation produces many B cells destined tofail and die, the recombination enzymes were turned back on in failing B cells,enzymes were turned back on, causing the cells' genetic material to recombine,generating new antibodies that were a perfect fit for the antigen threateningthem.

"We now know that the recombination enzymes are being expressed again inmature B cells; we know that the genes are being rearranged, and we know thatthis mechanism actually is responding to antigen exposure," Kelsoe said.

"This appears to be a rescue mechanism for cells that have been damagedby mutation," he suggested. "The germinal center is a Darwinian microcosm, andevery potential soldier is an investment worth protecting."

Kelsoe and colleagues' research was funded in part by the NationalInstitutes of Health, the Leukemia Society of America, the Arthritis Society,the Jeanne M. and Joseph P. Sullivan Foundation and the Santa Fe Institu