Chapter 37: Immunology of Hematopoietic Stem Cell Transplantation

INTRODUCTION

Hematopoietic stem cell transplantation (HSCT) has wide applications in the treatment of hematologic malignancies, congenital and acquired disorders of hematopoiesis, and autoimmune disease. Transplanted hematopoietic progenitors can reconstitute the full spectrum of hematopoietic cells in a recipient host, and can also confer immunologic antitumor activity. HSCT is therefore employed for both cellular replacement and for cancer immunotherapy. This chapter reviews the basic immunology of HSCT.

MAJOR CELLULAR TYPES

Following HSCT, donor hematopoietic progenitor cells migrate to the recipient bone marrow and differentiate to generate all cell types of the erythroid, myeloid, and lymphoid lineages. The following hematopoietic cell types are thought to play key physiologic roles:

• CD34⁺ cells: The population of cells containing the hematopoietic progenitors capable of repopulating the recipient marrow. HSCT grafts are usually quantified based on the CD34⁺ population. In certain selective cellular depletion protocols, donor hematopoietic cells can be purified for CD34⁺ cells prior to transplantation. Doses of more than or equal to 2 × 10⁶/kg (recipient weight) CD34-expressing progenitor cells are typically required in autologous or adult allogeneic adult donor prod-ucts. Requirements are approximately one log lower for umbilical cord products.

• B-cells: Lymphocytes whose chief role is to produce antibodies against specific antigens to mediate humoral immunity. The role of B cells in chronic graft-versus-host disease (cGVHD) has been recognized.

• CD8⁺ T cells: Cytotoxic T cells that recognize antigenic peptides presented on major histocompatibility (MHC) Class I proteins. In the presence of either a costimulatory signal or stimulatory cytokines (secreted by CD4⁺ Th and other cells), CD8⁺ T cells undergo clonal expansion and lyse their targets via the release of perforin and granzyme.

• CD4⁺ helper T (Th) cells: Helper T cells that can develop into either Th1 or Th2 effector T cells. Th1 cells support the cellular immune response by stimulating killing by macrophages and CD8⁺ T cells. Th2 cells support the antibody response by stimulating B-cell proliferation and antibody production. A third subset of Th cells (Th17 cells) has been identified although its role in HSCT is yet to be defined.

• Natural killer (NK) cells: Cytotoxic lymphocytes central to the innate immune response. NK cells kill cells that have lost cell-surface expression of self MHC I in a perforin- and granzyme-dependent manner. NK cells are also key effectors in humoral immunity, mediating antibody-dependent cellular cytotoxicity (ADCC).

• Regulatory (Treg) cells: A subset of CD4⁺ T cells that functions in a regulatory capacity to modulate the immune response and suppress autoimmunity. Ongoing clinical trials are exploring different ways to expand Treg cells to control GVHD.

• Dendritic cells: Antigen-presenting cells (APCs) that express high levels of both MHC I and MHC II and efficiently present antigens to T cells. Dendritic cells stimulate naïve T cells within lymphoid tissues. Dendritic cells within the thymus eliminate T cells that are selective for self-antigens through the process of negative ...