Robert S. Mittler, PhD - Basic Science Research Faculty

Robert S. Mittler, PhD

Associate Professor
Department of Surgery
Division of Transplantation and Emory Vaccine Center
Emory University School of Medicine

The focus of our research program is the study of mouse and human T-cell costimulation pathways that are essential for productive T-cell responses to foreign antigens. In this context, we hope to learn how to artificially regulate immune responses in humans, either to enhance the response in situations of immunodeficiency and tumorigenesis or to selectively diminish the response to organ transplantation or in autoimmune diseases. Enhancing the immune response. Recently we have focused upon T-cell activation regulated by the PD-1 receptor, a negative regulator of T cell activation, and the 4-1BB receptor an activator of T cells. PD-1 is a member of the CD28 family but unlike the CD28 T cell costimulatory receptor, its function is to counterbalance immune activation by turning it down. By blocking this signaling pathway, in conjunction with anti-4-1BB immunotherapy we hope to enhance the establishment of anti-tumor immunity to refractive, advanced neuroblastoma and Ewing¡¦s sarcoma, two of the most common and fatal childhood cancers. We further believe that this therapeutic strategy will lead to stronger and more durable immune responses to chronic viral infection.

Suppressing the immune response. Autoimmune disease and solid organ rejection are examples where immune suppression to self-antigens or alloantigens would be of immense clinical benefit. We, and others have shown that anti-4-1BB monoclonal therapy can either enhance, or suppress immune reactions in vivo. We have shown that anti-4-1BB treatment protects mice from, and reverses established SLE or RA two CD4 T cell and antibody mediated autoimmune diseases. Our recent studies have shown that the decision between immune suppression and immune enhancement depends on the timing of anti-4-1BB treatment. Given during antigen priming, or in the first two days of viral infection anti-4-1BB mAb treatment induces profound suppression of anti-viral immunity. When treatment was delayed 3-4 days anti-4-1BB treatment markedly enhanced anti-viral immunity. Our laboratory has spent the past year trying to understand the cellular and biochemical pathways that direct these two diametrically opposing outcomes. We have made progress by showing that immune suppression is IL-10, TNFĄ, and Fas-dependent. On the cellular level we have found that suppression is mediated through non-antigen dependent CD8 T cells in the host, and independent of antigen-specific T cells.

The CD137 receptor (AKA 4-1BB) is an activation inducible member of the Tumor Necrosis Factor Receptor Superfamily (TNFR). A key finding that we made has been that CD137 receptors in the mouse are preferentially used to activate CD8+ T-cells even though both CD4 and CD8 positive T cells express them. In collaboration with Drs. Chris Larsen and Tom Pearson we were also the first to show that administration of monoclonal anti-CD137 antibodies into mice receiving skin or cardiac allografts rejected their grafts much more rapidly than mice injected with a control mAb. Together with Dr. Ken Newell we showed that blockade of the CD137 signaling pathway in mouse small intestine allografts led to graft acceptance. One of our current goals in collaboration with Dr. Chris Larsen¡¦s group is to see whether the use of CD137 blocking fusion proteins can replicate the findings of Newell and Mittler in skin allograft transplants. Together with our colleague Dr. Lieping Chen now at Johns Hopkins SOM we were the first to show that anti-CD137 mAbs proved remarkably effective in completely eradicating established poorly immunogenic tumors in mice. Subsequently Dr. Mittler¡¦s group provided the first long-term comprehensive study that showed that anti-CD137 treatment reversed the course of established SLE and RA in mice and that the treated lupus mice that normally die before one year of age survived for over two years, the normal lifespan of a mouse. Collectively, these studies have led to the U.S. Patent office to award Dr Mittler and his collaborators three U.S. patents for the use of agents that bind to and affect CD137 function. The last of these was awarded in May 2007.

During the past six months Sefanie Kunze a German graduate student working as an exchange student in our lab has focused her research on the role of 4-1BB and 4-1BB ligand signaling pathways in a mouse model of Crohn¡¦s Disease (adoptive transfer of CD4+CD45RBhi T cells into C.B-17 SCID mice) an autoimmune inflammatory bowel disease (IBD). Stefanie injected CD4 T cell reconstituted SCID mice with either anti-4-1BB to exert an agonist affect on T cells or 4-1BB-Ig fusion protein that binds to antigen presenting cells that express 4-1BB ligand. Treatment with this reagent is expected to competitively block T cell expressed 4-1BB binding and thus block T cell activation. The mice were examined daily for signs of IBD which include significant weight loss and watery stools. Surprisingly, she found that either form of treatment rapidly induced an inflammatory skin disease and major hair loss in these mice that was first noticed around their eyes and later spread over the entire surface of the mouse. The kinetics of weight loss and diarrhea were likewise accelerated in anti-4-1BB or 4-1BB-Ig injected mice. Taken at face value, Stefanie¡¦s studies suggest that the 4-1BB/4-1BB ligand-signaling pathway may play an important role in maintaining peripheral tolerance and protection from autoimmune reactions. It is a bit too soon to draw any firm conclusions as to why these animals respond to treatment in this way, and one has to wonder if indeed blockade of 4-1BB ligand causes disease, is anti-4-1BB also acting in a blocking fashion? And why is it that neither 4-1BB nor 4-1BB ligand deficient mice develop autoimmune disease? On the other hand, the answer to that question may relate to the highly skewed nature of the immune system of the mice used in this model. Stefanie¡¦s observations were made in SCID mice. These animals have neither T cells other than a limit number of a select phenotype of CD4 T cells adoptively transferred into them and they are completely void of any B cells. At this point we cannot even say whether the skin disease is a result of unchecked adaptive immunity or whether it is solely dependent on an innate immune response. This question and others are now being addressed.

Recent Publications (2007-2008)

  • Niu, L., Strahotin, S., Hewes, B., Zhang, B., Spencer, T., Archer, D., Dillehay, D., Kwon, B.S., Chen, L., Vella, A.T., and Mittler, R.S. (2007).  
  • Cytokine-mediated disruption of lymphocyte trafficking, hematopoiesis, and induction of lymphopenia, anemia, and thrombocytopenia in anti-CD137 treated mice. J. Immunol. 178:4194.  
  • Irie J, Wu Y, Kachapati K, Mittler RS, Ridgway WM. (2007). Modulating Protective nd Pathogenic CD4+ Subsets via CD137 in Type 1 Diabetes. Diabetes 186-96.  
  • Laughlin EM, Miller JD, James E, Fillos D, Ibegbu CC, Mittler RS, Akondy R, Kwok W, Ahmed R, Nepom G. 2007. Antigen-Specific CD4+ T Cells Recognize Epitopes of Protective Antigen Following AVA Vaccination. Infect Immun. 75:4670.  
  • Zhang, B., Maris, C.H., Foell, J., Whitmire, J., Niu, L., Song, J., Kwon, B.S., Vella, A.T., Ahmed, R., Jacob, J., and Mittler, R.S. 2007. CD137 T cell costimulation-induced suppression or enhanced immune function during acute viral infection. J. Clin. Invest. 117:3029.  
  • Moens, L., Jeurissen A., Mittler R.S., Wuyts G., Michiels G., Boon L.,Ceuppens J.L., Bossuyt X. 2007. Distinct approaches to investigate the importance of the murine 4-1BB-4-1BBL interaction in the antibody response to Streptococcus pneumoniae. J Leukoc Biol. 82:638.  
  • McNamara, J.O., Kolonias, D., Pastor, F., Mittler, R.S., Chen, L., Giangrande, P.H., Sullenger, B., and Gilboa, E. 2008. Costimulation of CD8+ T cells and Inhibition of tumor growth with multivalent 4-1BB binding aptamers. J. Clin. Invest. 118:376.  
  • Robertson, S.J., Messer, R.J., Carmody, A.B., Mittler, R.S., Burlak, C., and Hazenkrug, K.J. 2008. CD137-costimulation of CD8+ T cells confers resistance to suppression by virus-induced regulatory T cells. J. Immunol. 180:5267.  
  • Lee, S-W, Park, Y., So, T., Kwon, B.S., Cheroutre, H., Mittler, R.S., and Croft, M. 2008. A novel regulatory role for 4-1BB and 4-1BBL in myelopoiesis and the development of dendritic cells. Nat. Immunol. 9:917