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Published online before print August 18, 2006
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Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
1 Correspondence: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. E-mail: hrosenberg{at}niaid.nih.gov
This manuscript was selected as Pivotal Advance because it highlights the importance of the leukocyte antigen CD69 in autoimmune phenomena. Dr. Sánchez-Madrid and colleagues have demonstrated the intriguing therapeutic potential of a specific Ig2a anti-CD69 monoclonal antibody that depletes CD69+ cells, thereby diminishing symptoms associated with the collagen-induced arthritis model of inflammatory joint disease.
Dr. Sánchez-Madrid, in this work, you characterize two distinct monoclonal antibodies, both directed against CD69. The Ig2a mAb 2.3 inhibits disease progression. Do you have any immediate or long-term plans to develop this concept or this specific reagent for human clinical use?
FSM: CD69 is expressed in recently activated T or B cells, so certainly any reagent that selectively depletes these CD69+ cells could be used for the induction of tolerance if used during the appropriate time frame. I believe that this strategy may be helpful in inhibiting the progression of RA in clinical settings, since the development of the disease is not linear and the CD69+ subtraction strategy could work if timed at the initial phase of each crisis or disease flare-up. There are even broader implications here, as the Ig2a mAb 2.3 might be used to induce tolerance in immune-mediated pathophysiologies such as allergy and graft rejection. I could even envision using this reagent for the elimination of tumor cells, perhaps in a manner similar to that described by Esplugues and colleagues [1 ]. In this work, the authors used an anti-CD69 mAb that recognized and reduced the expression of CD69. This did not result in target cell elimination, but rather resulted in NK cell activation and anti-tumor cytotoxicity. Clearly, given the range and breadth of potential applications, I do think that it is important to develop anti-CD69 antibodies for human clinical use.
The disease model featured in this manuscript, collagen-induced arthritis (CIA), is, as you have stated, a widely accepted model of inflammatory joint disease. Having worked extensively with this model, what do you see as the most and least helpful—or perhaps most and least clinically relevant—features of this disease model? Are there any specific improvements that could be made on this model or that might be developed in other models?
FSM: First, it is most important to recognize that the etiology of rheumatoid arthritis (RA) remains for the most part unknown. However, among several important clues, we know that T and B cells from individuals with RA can have specific reactivity against collagen type II (CII). In contrast, collagen-induced arthritis (CIA) is an autoimmune disease induced by a specific antigen. It is certainly possible that the two different disease processes are initiated by different mechanisms, although, there are a number of important similarities. For example, in RA, CII-specific T cells develop a Th1 response that controls B cell responses, and disease susceptibility is linked to specific class II molecules. Likewise, transgenic expression of HLA-DR1 and DR4 molecules, which are linked to susceptibility to RA in humans, also confers susceptibility to CIA. This model is actually an improved model for RA over those used more extensively in the past. It is particularly useful for determining the contribution of specific class II molecules in initiating and sustaining the symptomatology of RA.
The use of the CD69 gene-deleted mouse strain to create mouse anti-mouse CD69 monoclonal antibodies is very clever. Where did you get the idea to do this?
FSM: Actually, gene-deleted mice have been used previously by other investigators for immunization and generation of mouse antibodies specific for the eliminated antigen. For example, anti-mouse P selectin antibodies were generated by Massaguer and colleagues [2 ] in this fashion.
Dr. Sánchez-Madrid, can you tell the readers of Journal of Leukocyte Biology a bit about yourself, your education, and some of the highlights of your work?
FSM: I began my formal research career in 1977, at the Center of Molecular Biology in Madrid, where I worked on the biochemical and functional characterization of eukaryotic ribosomal proteins. I then did postdoctoral work from 1980–1983 in Boston with Dr. Timothy Springer’s group at the Harvard Medical School in Boston. We identified and characterized a number of leukocyte function-associated molecules that include the receptor-ligand pair LFA-2(CD2)-LFA3, and the first family of human integrins, the leukocyte β2 integrins. These adhesion molecules are essential in all processes of leukocyte adhesion and migration. While associated with Dr. Springer’s laboratory, I focused specifically on the molecular characterization of these adhesion molecules [3 , 4 ].
I am now a Senior Investigator in the Hospital Universitario de la Princesa in Madrid, Spain, a position I have held since 1985, and I am also Professor of Immunology in Universidad Autonoma de Madrid. I have continued on with my interest in leukocyte biology, and during the last twenty years, my research group has addressed many aspects of the molecular and functional mechanisms controlling leukocyte polarity, adhesion, migration and activation, and their relevance in inflammatory diseases [see reviews in 5 6 7 8 ].
You have had a very long and highly productive scientific career. Which of your original findings do you consider most important, long-lasting, or highest impact overall?
FSM: I consider that our main achievements to be 1) the identification and biochemical characterization of the integrin VLA-4 (
4β1) and its involvement in leukocyte intercellular interactions, and the role of 4 integrins in T cell migration and infiltration in several inflammatory diseases, including rheumatoid arthritis, nephritis, EAE; 2) the demonstration that leukocyte cell polarity could be induced by chemokines, and the identification of molecular components and function of two subcellular compartments, namely, the leading edge and the trailing edge or uropod; and 3) the biochemical and functional characterization of the earliest lymphocyte activation antigen, AIM-CD69, the cloning and determination of CD69 gene organization, and identification of its genetic regulatory elements.
Recently, our group was the first to generate CD69-deficient mice and to describe the in vivo physiological role of CD69 as a negative immunoregulatory molecule in both tumor-related and autoimmune inflammatory responses [reviewed in 9 ].
In that same line of thinking, I noticed that you are currently a member of Faculty of 1000 Biology. Members are asked to select and comment on papers of significant interest and impact, and thereby assist the general readership in sorting through the overwhelming mass of scientific publications emerging per unit time. Can you comment on this?
FSM: Faculty of 1000 Biology is a quite innovative and interesting task, one that facilitates the navigation through the rough waters of the scientific literature.
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subunits and sharing a common β subunit J. Exp. Med. 158,1785-1803
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