Disclosed is a method for producing regulatory T cells, the method comprising: (1) differentiating cells that can differentiate into regulatory T cells, into which an expression construct is introduced, into regulatory T cells, the expression construct comprising: (a) conserved non-coding sequence (CNS) 1, CNS2, and CNS3 of Foxp3 gene; (b) a promoter; and (c) a nucleic acid encoding FOXP3.
Also disclosed are regulatory T cells obtained by the method, and a pharmaceutical composition comprising the regulatory T cells.

The invention relates to an artificial T cell receptor, wherein an antigen binding domain of the artificial T cell receptor specifically binds a complement pathway protein, nucleic acids encoding such artificial T cell receptors and cells engineered to express such nucleic acids. The invention also relates to targeting polypeptides comprising an extracellular ligand binding domain and an intracellular domain comprising a transcription factor, and wherein the transcription factor is configured to be released upon binding of the ligand binding domain by a ligand. The invention also relates to cells engineered to express the artificial T cell receptor and the targeting polypeptide, particularly where expression of the artificial T cell receptor is operatively linked to binding of the ligand binding domain. The cells of the invention are useful in medicine, particularly in the treatment of inflammatory conditions.

Methods of preventing or treating autoimmune disease are disclosed. In some cases, subjects with having or at risk of developing autoimmune disease are identified as possessing one or more autoimmunity-susceptibility HLA alleles at one or more HLA loci. In many cases, the HLA loci are selected from Class I and Class II loci, for example Class I A, B, and C, and Class II DQ, DR, and DP. In many cases, subjects suffering from or at risk of developing an autoimmune disease may be administered a plurality engineered autologous HSCs modified to carry and express a variant susceptibility allele having at least one mutation in the antigen binding cleft that alters antigen binding and/or specificity of that variant HLA molecule. In many embodiments, the engineered HSCs are CD34+ immune cells that express one or more modified HLA proteins.

The present invention relates to regulatory T cell and uses thereof. By their immunosuppressive and anti-inflammatory activities, regulatory T cells play a central role in peripheral tolerance and thus critically prevent the development of autoimmune and inflammatory disorders. The inventors showed that Foxp3+CD4+ Tregs express high levels of LT, which negatively regulates their immunosuppressive signature. The inventors have demonstrated that the adoptive transfer of Tregs previously incubated with soluble lymphotoxin- receptor in mice protects from dextran sodium sulfate (DSS)-induced colitis. Thus, the number of cells to be injected in adoptive transfer may be reduced and a transfection or transduction step avoided, which represents a technical facilitation. In particular, the present invention relates to a method of treating or preventing autoimmune disorders and inflammatory-associated cancers in a subject in need thereof comprising the step of administrating to the subject a therapeutically effective amount of regulatory T cells which have been previously incubated with effective amount of soluble lymphotoxin- receptor.

A novel treatment for Graves' Disease (GD) is disclosed and described. Chimeric autoantigen receptor (CAAR) T cells are engineered using a CAAR construct causing thyroid stimulating hormone receptor (TSHR) epitope expression such that the engineered CAAR T cells serve as bait for autoreactive B cells. The engineered CAAR T cells specifically eliminate the autoreactive B cells, thus eliminating the causative factor for GD. Certain CAAR T cells are further engineered to incorporate bispecific LINK CAR technology to further require the presence of CD19 or BCMA to further increase CAAR T cell targeting specificity to autoreactive B cells and plasma cells.

Methods of stimulating or enhancing an immune response in a host are disclosed. The methods include contacting a monocyte with 15 kD granulysin thereby producing a monocyte-derived dendritic cell. In one example, the method further includes contacting the monocyte or monocyte-derived dendritic cell with a target antigen, such as a tumor antigen or an autoimmune antigen. In another embodiment, the method includes contacting the monocyte with an additional agent that enhances maturation of dendritic cells or induces immunological tolerance. The methods are of use in vivo, in vitro and ex vivo. In another aspect, the disclosure relates to compositions and methods for the treatment of tumors.

The present invention relates to tolerogenic mammalian dendritic cells (iDCs) and methods for the production of tolerogenic DCs. In addition, the present invention provides methods for administration of tolerogenic dendritic cells as well as particles containing oligonucleotides to mammalian subjects. Enhanced tolerogenicity in a host can be useful for treating inflammatory and autoimmune related diseases, such as type 1 diabetes.

A conditioned cell culture medium of CD11b.sup.low human macrophages or a biologically active fraction thereof can be prepared by a method that includes (i) culturing a population of human mononuclear cells of the monocyte/macrophage lineage for 5-7 days, so as to induce differentiation of the mononuclear cells to macrophages; (ii) incubating the macrophages obtained in (i) with apoptotic cells or in the presence of a pro-resolving lipid mediator to reduce the CD11b expression, thus obtaining a culture of CD11b.sup.low macrophages; and (iii) collecting the conditioned cell culture medium of CD11b.sup.low macrophages. Pharmaceutical compositions containing the CD11b.sup.low macrophages conditioned medium or a culture of CD11b.sup.low macrophages can be used in the treatment of cancer or fibrosis.

The present invention relates to compositions and methods for generating a modified T cell with a nucleic acid capable of downregulating endogenous gene expression selected from the group consisting of TCR chain, TCR chain, beta-2 microglobulin, a HLA molecule, CTLA-4, PD1, and FAS and further comprising a nucleic acid encoding a modified T cell receptor (TCR) comprising affinity for a surface antigen on a target cell or an electroporated nucleic acid encoding a chimeric antigen receptor (CAR). Also included are methods and pharmaceutical compositions comprising the modified T cell for adoptive therapy and treating a condition, such as an autoimmune disease.

Compositions and methods are provided for treating diseases associated with CD100, including certain autoimmune diseases, inflammatory diseases, and cancers. In particular, anti-CD100 monoclonal antibodies have been developed to neutralize CD100.