ROTRF Recognition Prize – Recognising Excellence in Organ Transplantation Research

13:25: Staphylococcal Infections as Barriers to Tolerance Induction

Dr Anita Chong, The University of Chicago, Chicago, USA

Staphylococcus aureus (SA) is a leading cause of nosocomial bloodstream, skin and soft-tissue, and lower respiratory infections. In the last decade the incidence and frequency of methicillin-resistant SA (MRSA) infections, causing skin infections, pneumonia, septic arthritis, foreign-body infections and sepsis, has increased exponentially among otherwise healthy individuals. We therefore focused our laboratory investigations on testing whether, and how, SA infections affect our ability to induce long-term allograft acceptance in mice. Our initial investigations led to the demonstration that SA infections at the time of transplantation prevent BALB/c skin allograft acceptance in C57BL/6 recipients treated with anti-CD154 + donor splenocyte transfusion (DST). The pro-inflammatory effects of IL-6, produced in response to SA infection, were necessary and sufficient in conferring resistance to anti-CD154/DST treatment.

Superantigens (SAg) secreted by Staphylococcus as well as Streptococcus bacteria have been shown to have profound effects on the T-cell repertoire by virtue of their ability to bind to select T cell receptor (TCR)-ß. We tested the impact of prior single exposure to staphylococcal enterotoxin A (SEA) and SEB on the induction of transplantation tolerance in mice. We observed that a single exposure to SEA (100 µg) or SEB (150 µg) 7 weeks prior to BALB/c skin allograft transplantation was able to prevent tolerance induction in C57BL/6 recipients treated with anti-CD154/DST. Phenotypic analysis at 5 weeks post-exposure to SEA, SEB or SA infection revealed a partial (40-60%) depletion of T cells expressing Vβ3 and Vβ11, Vβ3 and Vβ8, and Vß3, respectively. Notably, the percentage of activated/memory T cells expressing CD44 was not increased in T cells expressing Vß subunits targeted by SEA or SEB, suggesting that the depletion of specific Vß-expressing T cells following exposure to SAgs or SA infection induces homeostatic proliferation and the acquisition of memory-like phenotype in the remaining T cells.

Our observations underscore the potent effects that bacterial infections can have in preventing transplantation tolerance, either by stimulating the production of pro-inflammatory cytokines or by stimulating homeostatic proliferation and the generation of memory-like alloreactive T cells.

Anita Chong

Dr Anita Chong received her PhD from the John Curtin School of Medical Research at the Australian National University under the mentorship of Professor Christopher Parish. She went on to receive her post-doctoral training with Dr. Sidney Leskowitz at Tufts University in Boston, and Drs. Evan Hersh and William Grimes at the University of Arizona.Dr. Chong’s interest in transplantation emerged while she was a junior faculty member in the Department of Surgery, Rush Medical Center. There she teamed up with Dr. James Williams and the Rush Transplant Program to investigate the immunosuppressive and antiviral activities of leflunomide. In 2002, she was recruited to the Section of Transplantation at the University of Chicago, where she continued in depth studies on B cells in transplantation rejection and tolerance. She also initiated a collaborative research program with Dr. Marisa Alegre to investigate the impact of innate stimulation and bacterial infections in the induction and maintenance of transplantation tolerance. Dr. Chong has received significant research support from many funding sources over the past 20 years, primarily from the National Institutes of Health. She notes that she has been exceptionally fortunate to have been supported by the ROTRF at the initiation of each new research direction. In 2002, she received ROTRF funding for her efforts on understanding the pathogenicity of anti-Gal antibodies - she has extended those studies into investigations of the pathophysiology of antibodies and B cells in allotransplantation. In 2006, she also received ROTRF funding for studies on Staphylococcal bacterial infections and their impact on the induction of transplantation tolerance. These studies are revealing unexpected insights into the stability of tolerance and are leading to new areas of clinical investigation including Staphylococcal vaccine development.