The General Hospital Corporation

Columbia University

Genetics Institute, Inc.

Megan Sykes

David H Sachs

Thomas R Spitzer

Stanley F Wolf

Christian A Leguern

Gilles Jf Blancho

Hannes Kalscheuer

A Benedict Cosimi

Mohamed Sayegh

The invention provides for transgenic donor animals (e.g., pigs) whose cells, tissues and organs have a better long-term survival when transplanted into a human patient. The transgenic donor animal carries one or more human transgenes which is expressed only when the endogenous gene of the donor animal is knocked out shortly before a graft is harvested for transplantation. This 'genetic switch' allows the donor animal to remain healthy during the majority of its lifetime, while still allowing expression of the human transgene for optimal transplant tolerance in a human recipient. The transgene may encode a cytokine receptor, an adhesion molecule, or a complement regulatory protein.

Genetic modification of pigs for xenotransplantation

The invention provides an animal model and methods of generating large numbers of diverse, functional, na&#xef;ve T cells in mice using bone marrow cells from adult donors.

Generation of autologous T-cells in mice

A method of preparing a human recipient for a graft from a human which includes: administering donor peripheral blood progenitor cells to the recipient, and providing a minimally ablative.

Methods for human allografting

The inventors have discovered that hematologic disorders, e.g., both neoplastic (hematologic cancers) and non-neoplastic conditions, can be treated by the induction of mixed chimerism using myeloreductive, but not myeloablative, conditioning. Methods of the invention reduce GVHD, especially GVHD associated with mismatched allogeneic or xenogeneic donor tissue, yet provide, for example, significant graft-versus-leukemia (GVL) effect and the like.

Treatment of hematologic disorders

Antagonists of T cell migration are used to reduce GVHD in recipients of hematopoietic cell grafts. The administration of antagonists of T cell migration can be used in combination with conventional methods of bone marrow transplantation and in combination with the administration of donor leukocytes.

Blockade of T cell migration into epithelial GVHD target tissues as an approach to achieving anti-tumor effects against lymphohematopoietic malignancies without GVHD

Kits for treatment of hematologic disorders

A method of preparing a human recipient for a graft from a human which includes: inducing mixed chimerism in the recipient (e.g., by administering to the recipient irradiation or chemotherapy), administering thymic irradiation, administering an antibody that depletes T cells, administering donor hematopoietic progenitor cells to the recipient, and administering an immunosuppressant.

A method of inducing tolerance without whole body irradiation.

Mixed chimerism and tolerance

Use of blockade of costimulation and hematopoietic stem cell transplantation in the promotion of graft acceptance.

Costimulatory blockade and mixed chimerism in transplantation

The invention features a method designed to lengthen the time an implanted organ (a xenograft) survives in a xenogeneic host prior to rejection. Preparation of the recipient for transplantation includes the following steps: First, the recipient is administered low dose radiation. Second, an antibody preparation that binds T cells and NK cells is injected into the recipient. Third, natural antibodies are absorbed from the recipient's blood by hemoperfusion of an organ of the donor species. Fourth, hematopoietic stromal tissue of the donor species is administered to the recipient. Fifth, donor hematopoietic stem cells are injected into the recipient. Finally, the xenograft organ is implanted into the recipient mammal. Best results are obtained when all steps are used in combination.

Induced tolerance to xenografts

Use of the blockade of costimulation and hematopoietic stem cells in allograft transplantation.

Growing community of inventors

Charlestown, MA, United States of America

Megan Sykes