Drug – bio-affecting and body treating compositions – Lymphokine – Interferon
Reexamination Certificate
1999-05-19
2002-02-12
Saunders, David (Department: 1644)
Drug, bio-affecting and body treating compositions
Lymphokine
Interferon
C424S085600, C424S085700
Reexamination Certificate
active
06346243
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to the fields of neurology, immunology and protein chemistry. More specifically, the present invention relates to uses of oral Type I interferons to inhibit transplant rejection.
2. Description of the Related Art
Type I diabetes is a chronic disorder that results from autoimmune destruction of the insulin-producing pancreatic &bgr; cell. In the United States, the prevalence of type I diabetes by age 20 years is 0.26% and lifetime prevalence approaches 0.40%; thus approximately 1.5 million Americans have type I diabetes [1]. Once type I diabetes patients become insulin dependent, there is little therapeutic options except insulin replacement.
The Relevance of the NOD Mouse Model to Diabetes Mellitus:
The NOD mouse is a model of the human autoimmune disease type I diabetes [2-4]. The NOD mouse model is presumed to be T cell subset mediated and dependent on inflammatory cytokines for disease expression. Many key features of human type I diabetes are reflected in the NOD mouse: the development of insulinitis with infiltration of lymphocytes into the pancreatic islets of Langerhans that are selectively cytotoxic to the insulin producing &bgr; cells; the dependence of disease pathogenesis by T cells; and transmission of type I diabetes by hematopoietic cells in bone marrow [5-9].
Immunoregulatorv Cytokine Imbalances in Type I Diabetes:
Destruction of islet cells in NOD mice has been associated with a subset of T cells producing IFN-&ggr; [17]. IFN-&ggr; has been detected in lymphocytes infiltrating islets of human subjects with recent onset type I diabetes [18] and antibodies against IFN-&ggr; protect against diabetes development in NOD mice [19, 20] and BB rats [21]. IFN-&ggr; transgenic mice develop type I diabetes with inflammatory destruction of the islets [22, 23]. The incidence of type I diabetes correlates with IFN-&ggr;-producing islet T cells in NOD [24] and in NOD.scid mice [25]. This suggests that intraislet IFN-&ggr; may be critical in the development of diabetes mellitus (DM).
IFN-&agr; has been detected in &bgr; cells of animals and human subjects with recent onset type I diabetes [26, 27] and may elicit an immune mediated destruction of &bgr; cells; anti-IFN-&agr; antibody prevents this &bgr; cell damage [28]. Islet expression of IFN-&agr;, induced by polyinosinic-polycytidylic acid {poly (I:C)} or expressed from a transgene, precedes diabetes in both the BB rat and streptozotocin (STZ)-treated mice [29]. However, IFNs are well known to have dose related opposing effects on immune responses. In contrast to the results above, poly (I:C) can protect against overt type I diabetes in the NOD mouse [30] and can prevent the development of diabetes in BB rats by interfering with the development of insulitis [31]. Parenteral IFN-&agr; can decrease the development of spontaneous diabetes, the passive transfer of diabetes in NOD mice and decrease islet inflammation [32]. Therefore, IFN-&agr; is not intrinsically diabetogenic and may be protective. Indeed, moderate amounts of intraislet IFN-&agr; may be anti-inflammatory.
IL-4 and IL-10 cytokines can protect against the development of type I diabetes in the NOD mouse [33]. Transgenic NOD-IL-4 and rIL-4 administration to prediabetic NOD mice is protective against type I diabetes [34, 35], whereas the impairment of IL-4 production by PBMC or T cells was found in type I diabetes patients at diabetes onset [36]. IL-10 delays the onset of disease and reduces the incidence of diabetes, the severity of insulitis, prevents cellular infiltration of islet cells, and promotes normal insulin production by &bgr; cells [37, 38].
Adoptive Transfer of Protection Against Allograft Islet Rejection:
CD8+ cytotoxic T cell lines and clones generated from lymphocytic islet infiltrates can transfer diabetes rapidly without CD4+ T cells [42]. Islet-infiltrating lymphocytes from prediabetic SCD mice rapidly transfer diabetes to NOD.scid mice; cotransfer of splenocytes or CD4+, but not CD8+ spleen cells, together with islet infiltrating lymphocytes from prediabetics delayed the rapid transfer of type I diabetes, suggesting CD4+ cells also mediate immunoregulation [43, 44]. CD4+ T cell clones from unprimed NOD mice can protect against adoptive transfer of DM [45].
The effect of pro-inflammatory (IL-1, IL-2, IL-6, TNF-&agr;, type II IFN IFN-&ggr;) and anti-inflammatory (IL-4, IL-10, IFN-&agr;) cytokines in experimental models of allograft islet transplantation has been investigated. Enhanced expression of pro-inflammatory type II IFN-&ggr; contribute to graft destruction [48]. Pro-inflammatory cytokines IL-1&bgr;, TNF-&agr;, and IFN-&ggr; are cytotoxic to human islet 0-cells in vitro [49]. Non-function of isologous and allogeneic islet grafts is prevented by treatment with or increased IL-4 and IL-10 and decreased type II IFN IFN-&ggr; [33, 50]. Inhibition of NF-&kgr;B suppresses immune-mediated cell death in &bgr;-cells and protects from diabetogenic T cell immune attack in vivo. Therefore, increased IL-4/IL-10, inhibition of IFN-&ggr; and NF-&kgr;B activation may protect pancreatic &bgr;-cells [51].
Rejecting islet allografts contain a mixture of pro-inflammatory and anti-inflammatory cytokines such as IL-2 and IFN-&ggr; mRNA transcripts [52] and increased expression of IL-2, IL-4, TNF-&agr;, IFN-&ggr; and IL-10 mRNAs at the peak of the cellular infiltrate (on day 5) in islet allografts [53]. Allogeneic islet grafts showed increased IL-1 from 1 to 7 days, IL-2 and IFN-&ggr; transcripts at 1, 3, 5, and 7 days with a peak at day 5, IL-6 expression at 1 day, with constant IL-10 at all time points [54]. ICAM-1 antisense oligonucleotides can decrease increased IL-1 mRNA expression following kidney capsule islet transplantation and prolong allograft islet survival [55]. However, the simple Th1 to Th2 immune deviation does not blunt the severity of MHC-mismatched allograft rejection [50].
Type I Interferons:
In 1957 Isaacs and Lindenmann described a factor (interferon) produced by virus infected cells with rapid antiviral activity [57]. Type I IFNs are composed of two highly homologous proteins IFN-&agr; (leucocyte IFN) and IFN-&bgr; (fibroblast IFN) with similar biological properties [58], interact with the same cell receptor [59], and resist stomach acidity. Fifty to two hundred high affinity type I receptors are found on all lymphoid cells, including the gut associated lymphoid tissue (GALT) [60-62]. Therefore, type I IFNs are immunoactive endogenously produced proteins that can be active in the gut. Systemic effects may be achieved with IFN-&bgr; administered directly to the upper GI tract in experimental animal models of auto-immune disease and human auto-immune disease [63, 64] and does not result in detectable levels of IFN-&agr; in the blood [65-68] nor &bgr;
2
-microglobulin, neopterin, or 2-5A synthetase protein arkers of IFN absorption [69].
GALT (Gut Associated Lymphoid Tissue):
The afferent gut-associated lymphoid tissue has multiple types of constituent immune cells in lymphoid nodules termed Peyer's patches (PP) [78]. Peyer's patches contain T lymphocytes that are predominantly composed of the CD14+ T cells [79, 80] where regulatory cells can be generated [81, 82]. GALT activated lymphocytes, by virtue of their ability to circulate through the body, potentially can transfer their biological activities widely in the absence of circulating cytokines after contacting type I IFN in the gut-associated lymphoid tissue [83-87]. At their destination (islets), type I IFN-activated cells
Adler Benjamin Aaron
DeCloux Amy
Research Development Foundation
Saunders David
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