Areas of Interest
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.
Lab Rotation Projects
Elucidation of Factors that Determine Resistance or
Susceptibility to Allergic Asthma
The focus of work 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. Thus, we are
studying the development of functional capacity to present or
recognize antigen in early life by antigen presenting cells
(primarily Dendritic Cells or Macrophages), or T and B cells,
respectively. Our preliminary data suggests that maternal
transfer of allergen can protect offspring, whereas (depending
on whether the exposure is pre- versus post-natal) maternal
immunity can promote resistance or susceptibility to development
allergic airway disease. The goals of our current projects are
to define the cellular and molecular mechanisms responsible, and
studies along these lines achievable within the time frame of a
rotation will be pursued.
Publications
Selected Publications (trainees in bold):
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.
Matson AP, Zhu L, Lingenheld EG, Schramm CM, Clark RB,
Breen E, Selander DM and Puddington L. The impact of maternal
immunity on resistance to development of allergic airway
disease, submitted.
Brammer C, Lingenheld EG, Tanner C, Cose S,
Pizzo E, Khanna K, Zhu L and Puddington L. Lung antigen
presenting cells induce 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 TCRγδ
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, Lefrançois L, Lingenheld EG, Ishikawa H, Lewis
JM, Olson S, Suzuki K, Tigelaar RE, Puddington L. Enterocyte
expression of interleukin 7 induces development of
γδ T 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 (TCR)γδ and
TCRαβ lymphocytes in a murine model of
asthma. Am J Respir Cell Mol Biol. 2000 Feb;22(2):218-25.
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