Beth Israel Deaconess Medical Center, Inc.

The Beth Israel Hospital Association

The Brigham and Women's Hospital, Inc.

Other

The General Hospital Corporation

Cornell University

Children's Medical Center Corporation

Applied Research Systems Ars Holding N.v.

Beth Israel Hospital

Seragen, Inc.

Terry Barton Strom

Xin Xiao Zheng

Wlodzimierz Maslinski

Alan Steele

Vijay K Kuchroo

Sumone Chakravarti

Manikkam Suthanthiran

Chen Zhu

Yon Su Kim

Maria Koulmanda

Eugene K Cha

Alberto Sanchez-Fueyo

Sylvie Ferrari-Lacraz

Kenneth J Wieder

Catherine Anne Sabatos-Peyton

Jeffrey S Flier

Jean-Francois Bach

Towia Aron Libermann

Asher Schachter

Vicki E Kelley

Christiane Ferran

Jean C Nichols

Catherine Sabatos

Jennifer Meyers

Xian Chang Li

Yingyos Avihingsanon

Nali Ma

Miguel C Soares

Lauro Vasconcellos

Xin Xiao Zhen

Vicki E Rubin-Kelley

Towia Libermann

The specification provides compositions comprising chimeric proteins comprising AAT conjugated to an Fc region of an immunoglobulin. Methods for treating autoimmune disease, e.g., diabetes, e.g., Type 1 and Type 2 diabetes, are also provided.

&#x3b1;1-antitrypsin compositions and methods of treating autoimmune diseases

The invention relates to isolated polypeptides and nucleic acids encoding polypeptides which comprise a tim-3 IgV domain and a tim-3 intracellular domain, wherein the polypeptides do not comprise a tim-3 mucin domain or a tim-3 transmembrane domain. In addition, the invention relates to methods of modulating immune responses in a subject, comprising administering to the subject a therapeutically effective amount of an agent that modulates tim-3 activity. Immune responses include, but are not limited to, immune tolerance, transplantation tolerance, Th1 responses and Th2 responses.

TIM-3 ligands and methods of modulating immune responses

Prognostic methods useful in assessing patients who have received a transplant and reagents that can be used to carry out those methods are provided. The inventions are based, in part, on our analysis of gene expression in renal allografts and clinical parameters, i.e., variables associated with the donor, the recipient and/or the graft. The genes that can be assessed include those encoding agents that mediate inflammation, immune activation, and cell death (we may refer to these genes as 'inflammatory', 'immune' or &#x201c;cytoprotective&#x201d;). Surprisingly, the levels of gene expression could predict the occurrence of DGF, AR, and the quality of later graft function even when analyzed shortly after (e.g., after vascular anastomosis and tissue reperfusion). We also found that clinical parameters available at the time of transplantation correlate with decreased graft health and can be considered in combination with gene expression to evaluate a patient's risk for an adverse outcome.

Predicting graft rejection

Methods and compositions for treating patients (e.g., patients who are insulin resistant, patients who have diabetes, or are at risk for developing diabetes) are disclosed herein. The methods can include administration of an a1 antitrypsin (AAT) polypeptide or an agent, such as a nucleic acid molecule or organic compound, that promotes the expression or activity of a1-antitrypsin.

Compositions containing &#x3b1;-1-antitrypsin and methods for use

Tim-3 ligands and methods thereof

Disclosed herein are mutant IL-15 polypeptides and methods for using these polypeptides to modulate the immune response in a patient.

Antagonists of interleukin-15

The invention relates to methods of modulating immune responses in a subject, such as by administering to the subject agents which modulate tim-1, tim-2 or tim-4 activity, or which modulate the physical interaction between tim-1 and tim-4 or between tim-2 and a tim-2 ligand. Immune responses include, but are not limited to, autoimmune disorders, transplantation tolerance, and Th1 and Th2-mediated responses and disorders. The invention also relates to novel assays for identifying agents which modulate the physical interaction between tim-1 and tim-4. In addition, the invention relates to novel soluble tim-4 polypeptides and to nucleic acids which encode them.

Methods of modulating immune responses by modulating tim-1, tim-2 and tim-4 function

The present invention is based, in part, on expression studies of IL-2 and IL-15 receptor subunits by cycling T cells in vivo. In one embodiment, the invention generally features novel combinations of IL-2 and IL-15 antagonists and methods of suppressing the immune response by administering these antagonists. In each case, suppression is achieved by administration of a first agent that targets an IL-15 molecule or an IL-15 receptor (IL-15R) and a second agent that targets an IL-2 molecule or an IL-2 receptor (IL-2R). More generally, the invention features novel combinations of agents that, when administered to a patient (or to a transplant ex vivo), reduce the number of antigen-reactive T cells. For example, the invention features compositions (e.g., pharamaceutically acceptable compositions) that include two or more agents, each of which promote T cell death. Alternatively, the composition can contain at least one agent that promotes T cell death and at least one agent that inhibits T cell proliferation. The agent that promotes T cell death can promote AICD (activation induced cell death), passive cell death, ADCC (antibody dependent cell-mediated cytotoxicity) or CDC (complement directed cytotoxicity).

Modulation of IL-2- and IL-15-mediated T cell responses

Disclosed herein are therapeutic compositions containing agents that modulate the immune response in a patient.

Compositions and methods for achieving immune suppression

Disclosed are chimeric proteins having a cytokine fused to an enzymatically inactive polypeptide which increases the circulating half-life of the cytokine. The chimeric proteins are useful for treating, inhibiting, or preventing a variety of conditions, including septic shock, granulomatous disorders, Type I diabetes, and various cancers (e.g., multiple myeloma) in a patient.

Chimeric IL-10

Disclosure herein are mutant IL-15 polypeptides and methods for using these polypeptides to modulate the immune response in a patient.

Nucleic acids encoding antagonists of interleukin-15

The invention relates to methods of evaluating transplant rejection in a host comprising determining a heightened magnitude of gene expression of genes in rejection-associated gene clusters. The disclosed gene clusters include genes that are substantially co-expressed with cytotoxic lymphocyte pro-apoptotic genes, cytoprotective genes and several other cytokine and immune cell genes.

Measurement of protective genes in allograft rejection

Disclosed are chimeric proteins having IL-10 fused to an enzymatically inactive polypeptide which increases the circulating half-life of IL-10. The chimeric polypeptides are useful for treating or preventing septic shock, inhibiting the development of Type I diabetes, and treating multiple myeloma in a patient.

Treatment of diabetes

Growing community of inventors

Brookline, MA, United States of America

Terry Barton Strom