Prevention of Type 1 Diabetes with Major Histocompatibility Complex–Compatible and Nonmarrow Ablative Hematopoietic Stem Cell Transplants

  1. Georg F. Beilhack1,
  2. Rosa R. Landa1,
  3. Marilyn A. Masek2 and
  4. Judith A. Shizuru1
  1. 1Department of Medicine, Stanford University, Stanford, California
  2. 2Department of Pathology, Stanford University, Stanford, California
  1. Address correspondence and reprint requests to Judith A. Shizuru, PhD, MD, Division of Blood and Marrow Transplantation, Stanford University Medical Center, Stanford, CA 94305-5623. E-mail: jshizuru{at}stanford.edu

Abstract

Progression to hyperglycemia in young nonobese diabetic (NOD) mice is blocked by the transplantation of hematopoietic cells mismatched at the major histocompatibility complex (MHC). Because the NOD MHC class II allele, I-Ag7, is the primary disease susceptibility gene, it is logical to conclude that MHC-mismatched hematopoietic grafts prevent diabetes by replacement of this susceptibility allele on critical hematolymphoid populations. In this report, transplantation of MHC-matched purified hematopoietic stem cells (HSCs) pre-vented diabetes development in NOD mice, demonstrating that alleles of non-MHC background genes expressed on hematopoietic cells are sufficient to disrupt the autoaggressive process. Nonmarrow ablative conditioning was 100% protective, further showing that elimination of NOD hematopoiesis, including T-cells, was not required for the graft to block diabetes pathogenesis. The current standard clinical practice of hematopoietic cell transplantation uses donor/recipient pairs that are matched at the MHC. In our view, the principles established here using an MHC-matched engineered hematopoietic graft in conjunction with nonmarrow ablative conditioning to successfully block autoimmune diabetes sufficiently reduces the morbidity of the allogeneic transplantation procedure such that a similar approach can be translated to the treatment of human autoimmune disorders.

Footnotes

  • J.A.S. has received honoraria and consulting fees from Cellerant Therapeutics.

    The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted March 4, 2005.
    • Received October 6, 2004.
| Table of Contents