The overall goal of the research ongoing in my laboratory is to elucidate the contribution of maternal antigen or immune status in the susceptibility or resistance to development of allergic airway disease in offspring. It is evident from epidemiological studies that the risk for childhood asthma is increased by having a positive family history of asthma. In particular, allergic sensitization of the newborn is closely linked to maternal but not to paternal allergies. Our focus is on early life events (either pre-natal or early post-natal) that can result in T and B cell tolerance or immunity. Our hypothesis is that the environment in neonatal mice (determined by maternal immunity or passive transfer of antigen) is critical to immunological outcome, having life-long influences on development of immune responsiveness. We are identifying the cells responsible and the mechanisms by which they dictate functional commitment of the neonate to the development of, or protection from, atopy.

One strategy we are undertaking to advance this work is to characterize the antigen-presenting environment in pre- and post-natal life, with the focus on defining factors that dictate whether exposure to allergen in early life induces T cell sensitization or tolerance. The thinking is that in certain circumstances, T cell sensitization can occur in utero or in early post-natal life and that factors responsible for these circumstances have increased in the past 20 years. It has been proposed that this could explain the increased incidence of asthma and other inflammatory diseases. The challenge for scientists is to identify factors that control this process, with the ultimate goal of developing therapeutic strategies to reverse the progressive increase in disease. Our studies are focused on antigen-presenting cells such as dendritic cells (DCs) or macrophages, as they are known to direct the T cell responses to antigen throughout life, presumably including the pre- and post-natal period. In addition, we have developed transgenic models for evaluating T cell functional capacity at different ages, and in different environmental conditions, e.g. spleen or lymph node vs. lung or intestine in naïve mice or those with allergic airway disease. Our findings support the concept that it is not only the innate immune system that directs T cell responses, but also that T cell responses shape the development of the innate immune system.

Matson AP, Lingenheld EG, Zhu L, Breen E and Puddington L. Maternal Th1 immunity provides offspring with antigen-specific protection from development of allergic airway inflammation and allergen-specific IgE, (in preparation.)

Selander DM, Lingenheld EG, Schramm CM, Zhu L and Puddington L. Maternal breast milk antigen induces development of allergen-specific regulatory T cells to protect offspring from development of allergic airway disease,( in preparation.)

Brammer C, Lingenheld EG, Cose S, Pizzo E, Zhu L and Puddington L. A unique subset of lung antigen presenting cells induces T cell activation in the absence of clonal expansion: Novel strategy for control of mucosal T cell function, (submitted.)

Schramm CM, Puddington L, Wu C, Guernsey L, Gharaee-Kermani M, Phan SH, Thrall RS. Chronic inhaled ovalbumin exposure induces antigen-dependent but not antigen-specific inhalational tolerance in a murine model of allergic airway disease. Am J Pathol. 2004 Jan;164(1):295-304.

Lee SK, Kalinowski JF, Jastrzebski SL, Puddington L, Lorenzo JA. Interleukin-7 is a direct inhibitor of in vitro osteoclastogenesis. Endocrinology. 2003 Aug;144(8):3524-31.

Laky K, Lewis JM, Tigelaar RE, Puddington L. Distinct requirements for IL-7 in development of TCRgd cells during fetal and adult life. J Immunol. 2003 Apr 15;170(8):4087-94.

Wu CA, Puddington L, Whiteley HE, Yiamouyiannis CA, Schramm CM, Mohammadu F, Thrall RS. Murine cytomegalovirus infection alters Th1/Th2 cytokine expression, decreases airway eosinophilia, and enhances mucus production in allergic airway disease. J Immunol. 2001 Sep 1;167(5):2798-807.

Laky K, Lefrancois L, Lingenheld EG, Ishikawa H, Lewis JM, Olson S, Suzuki K, Tigelaar RE, Puddington L. Enterocyte expression of interleukin 7 induces development of gdT cells and Peyer's patches. J Exp Med. 2000 May 1;191(9):1569-80.

Schramm CM, Puddington L, Yiamouyiannis CA, Lingenheld EG, Whiteley HE, Wolyniec WW, Noonan TC, Thrall RS. Proinflammatory roles of T-cell receptor (TCRgd) and TCRab lymphocytes in a murine model of asthma. Am J Respir Cell Mol Biol. 2000 Feb;22(2):218-25.

Laky K, Lefrançois L, von Freeden-Jeffry U, Murray R and Puddington L. The role of IL-7 in thymic and extrathymic development of TCRgd cells, J Immunol. 1998 July 15; 161(2):707-713.