Getting to the source of 'self' protection

The human immune system performs constant surveillance of the body's internal environment, distinguishing "self" proteins from proteins that are foreign. Proteins recognized as "self" are considered safe and are therefore tolerated, while those considered "non-self" — and potentially harmful — are attacked.

For more than 30 years, the study of this intricate system has been a constant source of fascination for Eric Mickelson, a Clinical Research Division staff scientist. His work has centered on human leukocyte antigen (HLA) molecules, proteins that determine an individual's unique tissue type and form the very heart of the body's immune-surveillance system.

"The HLA system is the most polymorphic (diverse) genetic system known in man," Mickelson said.

Exploring how this diversity contributes to immune cells' ability to ignore "self" and attack "invaders" — and what happens when self-recognition goes awry — forms the core of Mickelson's work and that of the center's Human Immunogenetics Program, headed by Dr. John Hansen.

Mickelson began his career in 1969, when immunogenetics — the branch of genetics research focused on genes involved in regulating this critical immune response — was still in its fledgling stages. Characterizing the diversity of HLA genes, which are responsible for the variety of human-tissue types, has been central to the success of bone-marrow transplantation as a cure for leukemia and other blood cancers.

"Eric Mickelson has played a major role in the evolution of the HLA-typing program for the center from the very beginning of the program," said Dr. E. Donnall Thomas, the Nobel-prize-winning pioneer of bone-marrow transplantation and director emeritus of the Clinical Research Division.

"Eric worked with us at the old Public Health Hospital long before Fred Hutchinson existed. He has kept pace with the rapidly evolving, complex field — and he has always been a pleasure to work with."

The importance of tissue typing

When Mickelson began his career at the center, the importance of the HLA system in bone-marrow transplantation was generally recognized, but tissue-typing methods were still rudimentary.

"I began right around the time of the first stem-cell transplant. I was trained in microbiology, and had worked in a lab for some time, but I knew nothing about tissue typing. Nobody did — it was still so new," Mickelson said.

At the time, the tissue-typing program was part of the Adult Leukemia Research Program. In these early stages, researchers set the stage for defining the importance of matching HLA type between transplant donors and patients.

"Eric helped to establish the original tissue-typing laboratory here, which was essential for the transplant program from the very beginning," Hansen said. "Eric participated in a series of research studies that have advanced tissue-typing science and have improved the use of typing for transplantation."

In addition to their contributions to the success of the transplant program, Mickelson and his colleagues in the Immunogenetics Program also have conducted important fundamental studies on the genetics of the immune system.

When Mickelson began working at the center, researchers recognized that a complete characterization of the entire HLA system could not practically be completed by any one single source. Cataloging the diverse HLA system would require pooling together the minds and efforts of investigators around the world.

International Histocompatibility Working Group Workshops established the framework for this international cross-communication. Unlike many scientific meetings, where researchers present results of research projects near completion from their individual laboratories, the purpose of these international workshops was to organize collaborative projects that could share resources and generate data.

At the first meeting there were only 12 labs in attendance. Researchers brought their microscopes and the blood-cell samples they wanted to examine, working together to identify and characterize markers for distinguishing differences between HLA molecules.

In the 1990s, new molecular technology sent the field forward by a quantum leap. Now, the DNA blueprints of the HLA proteins could be dissected.

"DNA-based methods revolutionized HLA-typing," Mickelson said. "In 1984 — at the Munich workshop — the first description of molecular-typing methods was revealed. Rather than typing molecules based on elements at the cell surface, you could now extract the DNA from the nucleus of a cell and characterize the DNA sequence, typing directly based on the coding sequence. These methods are much more accurate and reliable."

By the 13th annual workshop in 2002 — held in Seattle and organized by Hansen — more than 1,000 different HLA gene variants had been identified and characterized. Planning for the workshop began in 1996, when Hansen set a precedent by securing funding from the National Institutes of Health (NIH) that would support the research and sustain scientific advances beyond the actual workshop.

"Eric was very involved in the workshop planning and was in charge of one of the core facilities — pulling together reference material and cell lines," Hansen said. "A core facility is essential for us to put together biological materials to be used by multiple investigators. Eric assembled more than 1,200 cell lines from all over the world. The cell lines have now become an important international resource."

"The goal of the workshop was first to assemble biological material and then systematically analyze genetic variation represented in many different reference cells to understand how genetic variation might account for disease susceptibility," Mickelson said. "Variation in HLA plays an especially critical role in individuals' susceptibility to infection, as well as to autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, diabetes and narcolepsy."

Working with Clinical Research Division investigator Dr. Lee Nelson, for example, Mickelson assembled a cell-line repository for investigating how HLA diversity contributes to susceptibility to rheumatoid arthritis.

The workshop also took steps toward amassing resources for studying the role of HLA molecules in bone-marrow transplantation, including a repository of around 3,000 cell lines and DNA from patients who have had a stem-cell transplant at the center. The repository is ever-growing important research resource, Mickelson said.

The repository provided Clinical Research Division investigator Dr. Effie Petersdorf with the material to analyze how HLA mismatches between patient and donor could affect transplant outcome, Mickelson said. He is currently working to establish these cell lines as shared resources for center investigators.

Mickelson cites teamwork as a key ingredient in the evolution of tissue-typing research during his tenure at the center.

"Don Thomas — and later, John Hansen — facilitated a challenging, intellectually stimulating environment," Mickelson said. "The team consists of people who could have gone anywhere and been successful, but Don Thomas kept them together. It has really been the perfect environment for me."