Inpharma 1240 - 3 Jun 2000 Inducing tolerance in BMT A treatment protocol combining high-dose bone marrow transplantation (BMT) with co-stimulatory blockade comprising anti-CD154 monoclonal antibody and cytotoxic T lymphocyte antigen 4 immunoglobulin (CTLA4Ig) achieves allogeneic bone marrow engraftment without cytoreductive host treatment in a murine BMT model, report researchers from the US and Austria. In this study, mice received bone marrow from fully major histocompatibility complex-mismatched donors followed by administration of intraperitoneal (IP) hamster monoclonal antibody against mouse CD154 on the day of BMT and IP mouse CTLA4Ig 2 days after BMT. Majority develop macrochimerism Two weeks after BMT and co-stimulatory blockade, 14/15 mice had developed multilineage macrochimerism; 9/14 mice experienced multilineage white blood cell chimerism for up to 30 weeks’ follow- up (long-term chimeras). No signs of graft-versus-host disease were detected in any of these mice. In contrast, no chimerism was detected in controls that underwent BMT alone. All long-term chimeras demonstrated donor-specific tolerance as assessed by primary skin grafting undertaken at 4 or 13 weeks after BMT. In another series of experiments, skin grafting was undertaken within 24 hours of mice undergoing BMT. The mice also received anti-CD154 monoclonal antibody and CTLA4Ig. Wider use of allogeneic BMT? Two weeks later, 7/9 mice demonstrated multilineage haematopoietic macrochimerism; 6/7 animals accepted donor skin grafts long-term (for > 100 days). The researchers comment that combining high-dose BMT with co-stimulatory blockade ‘could facilitate the more widespread use of allogeneic BMT in the treatment of non-malignant diseases, such as autoimmune diseases, certain hematologic conditions, and for transplantation tolerance’. Wekerle T, et al. Allogeneic bone marrow transplantation with co-stimulatory blockade induces macrochimerism and tolerance without cytoreductive host treatment. Nature Medicine 6: 464-469, Apr 2000 800820569 1 Inpharma 3 Jun 2000 No. 1240 1173-8324/10/1240-0001/$14.95 Adis © 2010 Springer International Publishing AG. All rights reserved

Inducing tolerance in BMT

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Inpharma 1240 - 3 Jun 2000

Inducing tolerance in BMTA treatment protocol combining high-dose bone

marrow transplantation (BMT) with co-stimulatoryblockade comprising anti-CD154 monoclonal antibodyand cytotoxic T lymphocyte antigen 4 immunoglobulin(CTLA4Ig) achieves allogeneic bone marrowengraftment without cytoreductive host treatment in amurine BMT model, report researchers from the US andAustria.

In this study, mice received bone marrow from fullymajor histocompatibility complex-mismatched donorsfollowed by administration of intraperitoneal (IP)hamster monoclonal antibody against mouse CD154 onthe day of BMT and IP mouse CTLA4Ig 2 days after BMT.

Majority develop macrochimerismTwo weeks after BMT and co-stimulatory blockade,

14/15 mice had developed multilineagemacrochimerism; 9/14 mice experienced multilineagewhite blood cell chimerism for up to 30 weeks’ follow-up (long-term chimeras). No signs of graft-versus-hostdisease were detected in any of these mice. In contrast,no chimerism was detected in controls that underwentBMT alone. All long-term chimeras demonstrateddonor-specific tolerance as assessed by primary skingrafting undertaken at 4 or 13 weeks after BMT.

In another series of experiments, skin grafting wasundertaken within 24 hours of mice undergoing BMT.The mice also received anti-CD154 monoclonalantibody and CTLA4Ig.

Wider use of allogeneic BMT?Two weeks later, 7/9 mice demonstrated multilineage

haematopoietic macrochimerism; 6/7 animals accepteddonor skin grafts long-term (for > 100 days).

The researchers comment that combining high-doseBMT with co-stimulatory blockade ‘could facilitate themore widespread use of allogeneic BMT in the treatmentof non-malignant diseases, such as autoimmunediseases, certain hematologic conditions, and fortransplantation tolerance’.Wekerle T, et al. Allogeneic bone marrow transplantation with co-stimulatoryblockade induces macrochimerism and tolerance without cytoreductive hosttreatment. Nature Medicine 6: 464-469, Apr 2000 800820569