Mechanisms of Tolerance Induction by Hematopoietic Chimerism: The Immune Perspective

Abstract

Hematopoietic chimerism is one of the effective approaches to induce tolerance to donor-derived tissue and organ grafts without administration of life-long immunosuppressive therapy. Although experimental efforts to develop such regimens have been ongoing for decades, substantial cumulative toxicity of combined hematopoietic and tissue transplants precludes wide clinical implementation. Tolerance is an active immunological process that includes both peripheral and central mechanisms of mutual education of coresident donor and host immune systems. The major stages include sequential suppression of early alloreactivity, establishment of hematopoietic chimerism and suppressor cells that sustain the state of tolerance, with significant mechanistic and temporal overlap along the tolerization process. Efforts to devise less toxic transplant strategies by reduction of preparatory conditioning focus on modulation rather than deletion of residual host immunity and early reinstitution of regulatory subsets at the central and peripheral levels. Stem Cells Translational Medicine 2017;6:700-712.

Keywords: Central tolerance; Hematopoietic cell transplants; Hematopoietic chimerism; Peripheral tolerance; Regulatory T cells; Transplant tolerance.

Figure 1

Milestones in development of approaches to induction of tolerance by hematopoietic chimerism. Efforts to decipher the nature of the immune system extend over more than a century, with gradual transition from cellular to molecular research and characterization. This knowledge has been adopted to develop strategies to induction of transplant tolerance by hematopoietic chimerism for more than six decades. The conceptual transitions from aggressive conditioning and full chimerism to reduced intensity conditioning and mixed or transient donor chimerism follow the evolution of experimental approaches to immunosuppression. The general trend is reduction of preparatory conditioning to a yet undefined minimum that prevents acute rejection and is permissive to hematopoietic engraftment. Current efforts are directed to develop approaches to immunomodulation and diversion of the function of immune cells without depletion. Abbreviations: ATG, anti‐thymocyte globulin; TBI, total body irradiation, TLI, total lymphoid irradiation.

Figure 2

Inductive interactions in immune activation. In first stage, indirect antigen‐presentation in the context of MHC compatibility and direct presentation in the context of incompatible MHC induce T‐cell receptor‐dependent T‐cell stimulation (signal 1). The same interactions serve for delivery of costimulatory signals (signal 2) and T‐cell activity is further activated by cytokines and environmental factors (signal 3). Uncontrolled reactivity results in adverse immune reactivity: of residual host immune cells as mediators of acute HVG rejection and of donor T cells as mediators of graft versus host disease. Abbreviations: HVG, host versus graft; GvH, graft versus host; MHC, major histocompatibility complex; TAA, tissue‐associated antigens; miHA, minor histocompatibility complex antigens.

Figure 3

Immune profiles of the various conditioning strategies. Myaloablation eradicates host immunity and activity of hematopoietic progenitors, awarding an advantage to creation of full donor chimerism. The nature of conditioning affects primarily early reconstitution, which is polarized to either dominant donor or host stable multilineage chimerism at later periods. Reduced intensity conditioning includes lower doses of preparatory agents, selective lymphoablation by immunosuppressive therapy, selective lymphoreduction and cytoreduction (aiming to free space in the bone marrow), and modulation of immune responses without cell depletion. Notably, residual host hematopoietic progenitors exposed to conditioning agents engraft slower that exposed donor progenitors.

Figure 4

Stages of immune reconstitution for induction of transplant tolerance by hematopoietic chimerism. Following induction of peripheral host anergy by immunosuppressive therapy, stepwise immune reconstitution from the grafted donor and residual host progenitors generates mutually tolerant T cells. Delayed recovery of the thymus and reconstitution of suppressor subsets (Treg) contribute to maintenance of the state of tolerance. Peripheral and central mechanisms are closely interrelated and the relative impact within the tolerizing process varies according to the nature of preparatory conditioning and the quality of immunohematopoietic reconstitution. The possible outcomes in reference to the goal of the procedure and potential complications range from optimal tolerance without graft versus host disease (GVHD) to worst case scenario of nontolerant state with severe GVHD. Abbreviation: HSPC, hematopoietic stem and progenitor cells.

Figure 5

Variability in types of chimerism compatible with induction of transplant tolerance as detected in peripheral blood. Donor chimerism may replace or coexist at variable ratios with host immunohematopoietic system, make a small or transient contribution of immune and hematopoietic reconstitution. The lower panel provides a rough time scale for sequential donor‐derived reconstitution from different subsets of progenitor and stem cells.