Chemistry: molecular biology and microbiology – Animal cell – per se ; composition thereof; process of... – Primate cell – per se
Reexamination Certificate
1996-02-28
2004-11-23
Park, Hankyel T. (Department: 1648)
Chemistry: molecular biology and microbiology
Animal cell, per se ; composition thereof; process of...
Primate cell, per se
C435S007240, C435S372000, C435S373000
Reexamination Certificate
active
06821778
ABSTRACT:
1. INTRODUCTION
This invention relates to methods of using human dendritic cells to present antigens for the induction of antigen-specific T cell-mediated immune responses. In particular, it relates to the isolation of dendritic cells from human blood, exposing the cells to antigens, co-culturing the antigen-pulsed dendritic cells with &ggr;&dgr;-T cell receptor-positive-T cells (&ggr;&dgr;-TCR
+
T cells) obtained from unprimed or weakly primed individuals for the stimulation of antigen-specific T cell proliferative and cytotoxic activities. The dendritic cell antigen presentation system described herein has a wide range of applications, including but not limited to, activation and expansion of large numbers of antigen-specific major histocompatibility complex-unrestricted T cells for use in adoptive cellular immunotherapy against infectious diseases and cancer.
2. BACKGROUND OF THE INVENTION
2.1. Generation of an Immune Response
The introduction of a foreign antigen into an individual elicits an immune response consisting of two major components, the cellular and humoral immune responses, mediated by two functionally distinct populations of lymphocytes known as T and B cells, respectively. The T cells nay be further divided into two subsets by function and phenotype. A subset of T cells responds to antigen stimulation by producing lymphokines which “help” or activate various other cell types in the immune system. Another T cell subset is capable of developing into antigen-specific cytotoxic effector cells, being able to directly kill antigen-positive target cells. On the other hand, the B cell response is primarily carried out by secretory proteins, antibodies, which directly bind and neutralize antigens.
Helper T cells (TH) can be distinguished from classical cytotoxic T lymphocytes (CTL) and B cells by their cell surface expression of a glycoprotein marker termed CD4. Although the mechanism by which CD4
+
TH function has not been fully elucidated, the existence of functionally distinct subsets within the CD4
+
T cell compartment has been reported (Mosmann and Coffman, 1989, Ann. Rev. Immunol. 7:145-173). In the mouse, type 1 helper T cells (TH1) produce interleukin-2 (IL-2) and &ggr;-interferon (&ggr;-IFN) upon activation, while type 2 helper T cells (TH2) produce IL-4 and IL-5. Based on the profile of lymphokine production, TH1 appear to be involved in promoting the activation and proliferation of other T cell subsets including CTL, whereas TH2 specifically regulate B cell proliferation and differentiation, antibody synthesis, and antibody class switching. Some CD4
+
T cells, like CD8
+
CTL, appear to be capable of cytotoxic effector function.
A second T cell subpopulation is the classical CTL which express the CD8 surface marker. Unlike most TH, these cells display cytolytic activity upon direct contact with target cells, although they are also capable of producing certain lymphokines. In vivo, CTL function is particularly important in situations where an antibody response alone is inadequate. There is a preponderance of experimental evidence that CTL rather than B cells and their antibody products play a principal role in the defense against viral infections and cancer.
A salient feature of both T and B cell responses is their exquisite specificity for the immunizing antigen; however, the mechanisms for antigen recognition differ between these two cell types. B cells recognize antigens by antibodies, either acting as cell surface receptors or as secreted proteins, which bind directly to antigens on a solid surface or in solution, whereas T cells only recognize antigens that have been processed or degraded into small fragments and presented on a solid phase such as the surface of antigen-presenting cells (APC). Additionally, antigenic fragments must be presented to T cells in association with major histocompatibility complex (MHC)-encoded class I or class II molecules. The MHC refers to a cluster of genes that encode proteins with diverse immunological functions. In man, the MHC is known as HLA. Class I gene products are found on all somatic cells, and they were originally discovered as targets of major transplantation rejection responses. Class II gene products are mostly expressed on cells of various hematopoietic lineages, and they are involved in cell-cell interactions in the immune system. Most importantly, MHC-encoded proteins have been shown to function as receptors for processed antigenic fragments on the surface of APC (Bjorkman et al., 1987, Nature 329: 506-512).
Another level of complexity in the interaction between a T cell expressing an &agr;&bgr;-T cell receptor and an antigenic fragment is that it occurs only if the MHC molecules involved are the same on the APC and the responding T cells. In other words, a T cell specific for a particular antigenic epitope expresses a receptor having low affinity for self MHC proteins, which when such MHC proteins on APC are occupied by the epitope, engage the T cell in a stronger interaction leading to antigen-specific T cell activation. The phenomenon of a T cell reacting with a processed antigen only when presented by cells expressing a matching MHC is known as MHC-restriction. This requirement presents a practical limitation to the use of MHC-restricted T cells in cellular immunotherapy since the T cells must be matched at the MHC with a recipient's target cells for them to be effective.
The specificity of T cell immune responses for antigens is a function of the unique receptors expressed by these cells. The T cell receptor (TCR) is structurally homologous to an antibody; it is a heterodimer composed of disulfide-linked glycoproteins. Four TCR polypeptide chains known as &agr;, &bgr;, &ggr;, and &dgr; have been identified, although the vast majority of functional T cells including both CD4
+
T
H
and CD8
+
CTL, express the &agr;&bgr; heterodimeric TCR. Transfer of &agr; and &bgr; genes alone into recipient cells was shown to be both necessary and sufficient to confer antigen specificity and MHC-restriction (Dembic et al., 1986, Nature 320: 232-238). Thus, the &agr;&bgr; TCR appears to be responsible for recognizing a combination of antigenic fragment and MHC determinants. In this regard, the ability of an antibody specific for MHC class I or class II molecules to inhibit the antigen reactivity of a particular T cell population is often used as an indication that the T cells express &agr;&bgr;-TCR.
The apparent basis of MHC restriction is that CD4
+
T cells express &agr;&bgr; TCR which recognize antigenic fragments physically associated with MHC class II proteins, while the TCR on CD8
+
CTL recognize MHC class I-associated fragments. Thus, CD4
+
T cells can recognize only a restricted class of APC that are class II
+
, whereas CD8
+
CTL can interact with virtually any antigen-positive cells, since all somatic cells express class I molecules. CD4
+
CTL have been identified, and they are MHC class II restricted, and lyse target cells only if the latter express self-MHC class II determinants associated with specific antigenic fragments. Both CD4 and CD8 molecules also contribute to this interaction by binding to monotypic determinants on the MHC class II and I molecules, respectively.
A second type of TCR composed of &ggr;&dgr; heterodimers is expressed by a small percentage of T cells. Approximately 10% of T cells in the peripheral blood express the &ggr;&dgr;-TCR, and a larger percentage of T cells in certain epithelial tissues such as the gut and skin are reported to be &ggr;&dgr;-positive (Allison and Havran, 1991, Annu. Rev. Immunol. 9:679-705). Although &ggr;&dgr;-TCR
+
T cells differentiate in the thymus and appear to be able to respond to foreign antigens in a manner analogous to &agr;&bgr;-TCR-bearing T cells, the physiologic role of &ggr;&dgr;-T cells is poorly understood. Some studies have shown that functionally active &ggr;&dgr;-T cells can be cytolytic in an MHC unrestricted manner. If so, it may be possible to utilize a
Engleman Edgar G.
Fagnoni Francesco
Markowicz Sergiusz
Mehta Anita
Takamizawa Masaru
Dehlinger Peter J.
Park Hankyel T.
Perkins Coie LLP
The Board of Trustees of Leland Stanford Junior University
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