Humanized Mouse Models of Severe Combined Immunodeficiency

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DESCRIPTION (provided by applicant): Severe combined immunodeficiency (SCID) is a heterogeneous group of fatal congenital disorders characterized by the absence of T lymphocytes. T cells develop from bone marrow derived T progenitors that migrate to the thymus and differentiate before export to the blood. The most common form, X-linked SCID, is caused by lack of common gamma chain (?c) expression. Because mouse models for X-linked SCID are lacking, we still know surprisingly little about why lack of ?c impairs T cell development. The goal of this project is to determine the stage(s) at which T cell development in the absence of ?c is aberrant, at the level of T progenitor generation, thymus seeding and/or intrathymic development. We hypothesize that T development will be affected at the T progenitor stage and more severely affected at an early stage of intrathymic development. We further hypothesize that failure of differentiation, rather than defects in proliferation/survival, causes an absolute block in development and that this failure can be rescued by reconstituting the specific components of the ?c signaling pathway. In Aim 1, we will examine the normal expression of ?c in human T cell progenitors and investigate whether T progenitors are present in the bone marrow of patients with X-linked SCID. In Aim 2 and Aim 3, we will create humanized mice bearing ?c deficient immune systems, using a new strain of NOD-scid immunodeficient mice that can support human T cell differentiation in vivo (NOD/scid Il2rgnull). In Aim 2 we will reconstitute NOD/scid Il2rgnull mice with normal human bone marrow in which ?c has been knocked down by lentiviral expression of short hairpin RNA. Using these "?c knockdown mice," we will analyze bone marrow and thymus, and characterize the precise nature of the T cell differentiation block. In Aim 3 we will reconstitute NOD/scid Il2rgnull mice with bone marrow from patients with X-linked SCID. We will then use this "humanized X-SCID" mouse model to test whether activation of the STAT5 pathway or Akt pathway can restore T cell development in the absence of ?c. Humanized mice will give us the ability to propagate normal and aberrant human immune systems in a tractable animal system and bridge the gap that currently exists between mouse models and human disease. We believe this model will also ultimately lead to discovery of novel genes critical for human immune development and novel therapies for SCID. PUBLIC HEALTH RELEVANCE: T cells are an essential component of the immune system. Congenital absence of T cells (severe combined immunodeficiency or SCID) or acquired immunodeficiency (such as in AIDS, following bone marrow transplantation or after cancer treatment) all cause significant morbidity and mortality. By studying why T cells fail to develop in the most common form of SCID, we hope to develop therapies that enhance T cell development and thus in turn enhance T cell dependent immune responses.