Professor Mack’s laboratory focuses on deciphering the role of different immune cells at a molecular level and their impact on disease and pathology. Of particular interest, is to understand the role of basophils, monocytes, and collagen-producing hematopoietic cells in autoimmunity, transplant rejection, and fibrosis. The ultimate goal of the team’s research is to develop new therapeutic approaches for clinical application. The following projects are currently underway:

Basophils as regulators of immune responses and fibrosis

Professor Mack’s team have identified previously obscure antigen-capturing cells as basophils. In preimmunized mice only two cell populations are able to bind (capture) significant amounts of antigen on their cell surface. These are; antigen-specific B cells that capture the antigen with the specific B cell receptor; and basophils that capture antigens using antigen-specific IgE bound to the high affinity FceRI-receptor. In mice the binding of antigens activates basophils to immediately release IL-4 and IL-6. During a secondary or memory immune response, basophils are responsible for the immediate production of IL-4 following the injection of the antigen. This leads to an enhancement of humoral memory immune responses. Basophils also constitute an important source of IL-4 in primary immune responses, as they can also be activated by various cytokines and other molecules like proteases from parasites. In conclusion, it is quite clear that basophils are an important source of the initial IL-4 which is required to induce a Th2 differentiation. By enhancing humoral and Th2 immune responses, basophils play a critical role in the development of diseases like rheumatoid arthritis and lupus nephritis. Moreover, due to the profibrotic properties of IL-4, basophils are also involved in fibrogenesis—as shown in chronic transplant rejection models. Going forward, work will continue into analyzing the role of basophils in autoimmunity and fibrosis.

The role of IL-3 in autoimmunity, inflammation, and fibrosis

IL-3 belongs to the family of hematopoietic cytokines which also include GM-CSF and IL-5. For many years IL-3 was considered to be mainly involved in hematopoiesis and defense against parasites. Professor Mack’s team have now identified IL-3 to be an essential cytokine in systemic lupus erythematodes (SLE), rheumatoid arthritis, multiple sclerosis, and fibrosis. Additionally, they have also proven that T cells are the main source of IL-3 in murine models of inflammation. Blockading IL-3 with an antibody or genetically deleting it altogether has been found to markedly improve disease activity in mouse models for systemic lupus (MRL-lpr), rheumatoid arthritis (collagen-induced arthritis, CIA), and multiple sclerosis (experimental autoimmune encephalitis, EAE). Along with others, the team have found that IL-3 is an essential inductor cytokine for several classical proinflammatory cytokines such as; IL-6, TNF-alpha, and IL-1. In addition, IL-3 is essential for the mobilization of innate immune cells in the bone marrow during inflammation. All in all, it is quite clear that the blockading of IL-3 interferes with multiple proinflammatory mechanisms. Reserach so far reveals that a blockade or deficiency of IL-3 is very well tolerated in mice. And that in contrast, an injection of recombinant IL-3 significantly increases disease activity in mouse models and induces polyarthritis in healthy rhesus monkeys.

In humans, IL-3 activates plasmocytoid dendritic cells (pDC), monocytes, basophils, mast cells, B cells, and endothelial cells. Plasmacytoid dendritic cells are the most important producers of type I interferons that play a central role in the pathogenesis of systemic lupus and also fibrosis. In endothelial cells, IL-3 induces the upregulation of E- and P-selectins—thus enabling the transendothelial migration of leukocytes. In the laboratory, the team have generated multiple monoclonal antibodies against human IL-3 and are currently analyzing the expression of IL-3 in patients with autoimmune and inflammatory diseases.

Fibrogenesis mechanisms with a focus on kidney and allograft fibrosis

Over recent years, the Institute's scientists and many others have been able to establish that collagen-producing cells in the kidney are derived from various cellular sources, including resident mesenchymal fibroblasts, pericytes, bone marrow-derived cells, tubular epithelial cells, and endothelial cells. Collagen-producing bone marrow-derived cells are frequently called fibrocytes. To this end, the team are investigating; the extent to which fibrocytes contribute to renal and allograft fibrosis; how they migrate into the organs; and how they are activated to produce collagen. Researchers are also investigating the functional relevance of cell-type-specific collagen production in the kidney and in cardiac allografts.

Functional analysis of monocyte subsets

Mouse and human monocytes can be divided into CCR2+ and CCR2- monocytes. The majority of monocytes comprise CCR2+ and are frequently found in inflamed tissue. Using a variety of animal models and antibodies to specifically deplete these cells, the LIT’s scientists and others have shown that CCR2+ monocytes contribute significantly to inflammation and tissue destruction. With this well proven, the team are currently developing new tools to specifically deplete CCR2+ monocytes in patients with inflammatory and autoimmune diseases.

Discover more by visiting Professor Mack’s dedicated UKR research page!

Here is a selection of the most important publications from the last few years:

Renner, K., T. Schwittay, S. Chaabane, J. Gottschling, C. Müller, C. Tiefenböck, J. N. Salewski, F. Winter, S. Buchtler, S. Balam, M. V. Malfertheiner, M. Lubnow, D. Lunz, B. Graf, F. Hitzenbichler, F. Hanses, H. Poeck, M. Kreutz, E. Orso, R. Burkhardt, T. Niedermair, C. Brochhausen, A. Gessner, B. Salzberger and M. Mack (2021). “Severe T cell hyporeactivity in ventilated COVID-19 patients correlates with prolonged virus persistence and poor outcomes.” Nat Commun 12(1): 3006.

Buchtler, S., A. Grill, S. Hofmarksrichter, P. Stockert, G. Schiechl-Brachner, M. Rodriguez Gomez, S. Neumayer, K. Schmidbauer, Y. Talke, B. M. Klinkhammer, P. Boor, A. Medvinsky, K. Renner, H. Castrop and M. Mack (2018). “Cellular Origin and Functional Relevance of Collagen I Production in the Kidney.” J Am Soc Nephrol 29(7): 1859-1873.

Renner, K., S. Hellerbrand, F. Hermann, C. Riedhammer, Y. Talke, G. Schiechl, M. R. Gomez, S. Kutzi, D. Halbritter, N. Goebel, H. Brühl, R. Weissert and M. Mack (2016). “IL-3 promotes the development of experimental autoimmune encephalitis.” JCI Insight 1(16): e87157.

Schiechl, G., F. J. Hermann, M. Rodriguez Gomez, S. Kutzi, K. Schmidbauer, Y. Talke, S. Neumayer, N. Goebel, K. Renner, H. Bruhl, H. Karasuyama, K. Obata-Ninomiya, K. Utpatel, M. Evert, S. W. Hirt, E. K. Geissler, S. Fichtner-Feigl and M. Mack (2016). “Basophils Trigger Fibroblast Activation in Cardiac Allograft Fibrosis Development.” Am J Transplant 16(9): 2574-2588.

Denzel, A., U. A. Maus, M. R. Gomez, C. Moll, M. Niedermeier, C. Winter, R. Maus, S. Hollingshead, D. E. Briles, L. A. Kunz-Schughart, Y. Talke and M. Mack (2008). “Basophils enhance immunological memory responses.” Nat Immunol 9(7): 733-742.