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Production of IFN- and IL-10 to Shigella Invasins by Mononuclear Cells from Volunteers Orally Inoculated with a Shiga Toxin-Deleted Shigella dysenteriae Type 1 Strain¹

Taraz Samandari^*, Karen L. Kotloff^*, Genevieve A. Losonsky^*, William D. Picking, Philippe J. Sansonetti, Myron M. Levine^* and Marcelo B. Sztein^2,*

^* Center for Vaccine Development, Departments of Pediatrics and Medicine, University of Maryland School of Medicine, Baltimore, MD 21201; Department of Biology, St. Louis University, St. Louis, MO 63103; and Unité de Pathogénie Microbienne Moléculaire, Unité 389, Institut Nationale de la Santé et de la Recherche Médicale, Institut Pasteur, Paris, France

Volunteers were orally administered invasive, non-Shiga toxin-producing Shigella dysenteriae 1 to establish a challenge model to assess vaccine efficacy. In stepwise fashion, four separate groups were given 3 x 10², 7 x 10³, 5 x 10⁴, or 7 x 10⁵ CFU. Using PBMC, proliferative responses and cytokine production were measured to S. dysenteriae whole-cell preparations and to purified recombinant invasion plasmid Ags (Ipa) C and IpaD. Anti-LPS and anti-Ipa Abs and Ab-secreting cells were also evaluated. Preinoculation PBMC produced considerable quantities of IL-10 and IFN-, probably secreted by monocytes and NK cells, respectively, of the innate immune system. Following inoculation, PBMC from 95 and 87% of volunteers exhibited an increased production of IFN- and IL-10, respectively, in response to Shigella Ags. These increases included responses to IpaC and IpaD among those volunteers receiving the lowest inoculum. No IL-4 or IL-5 responses were detected. Whereas there were no Ab or Ab-secreting cell responses in volunteers receiving the lowest inoculum, other dose groups had moderate to strong anti-LPS and anti-Ipa responses. These results suggest that in humans, type 1 responses play an important role in mucosal and systemic immunity to S. dysentariae 1.