FIGURE 3. Mechanisms by which HCT might ameliorate autoimmune diseases.

These mechanisms are not mutually exclusive. Donor-derived cells are shown in green and host-derived cells are shown in red. a, Immunomodulation by immunosuppressive conditioning: potent immunosuppressive treatments such as total body irradiation (TBI), cyclophosphamide (CY), anti-CD2 antibodies (anti-CD2), anti-CD52 antibodies (anti-CD52), fludarabine and anti-thymocyte globulin (ATG) can eliminate the majority of B and T cells. In addition to alloreactive and autoreactive memory B cells and T cells, other T and B cells are depleted. b, Immune-mediated destruction of autoreactive cells (graft-versus-autoimmune host T and B cells). Donor T cells recognize alloantigens and destroy residual memory B and T cells. This mechanism is applicable to allo-HCT only. c, Deletion of alloreactive and autoreactive T cells in the thymus. If both donor and host cells contribute to haematopoiesis and to the antigen-presenting cell (APC) pool in the thymus, the new T-cell repertoire generated in the recipient thymus is deleted of T cells recognizing both allo- and autoantigens expressed by haematopoietic cells of both origins. d, Induction of anergy and deletion of autoreactive and alloreactive T cells in the periphery. Costimulatory blockade of the CD40−CD154 and CD28−CD80−CD86 pathways in concert with allogeneic BMT can overcome the T-cell barrier to allo-HSC engraftment, which in turn quickly produces donor-specific tolerance and could tolerize cross-reactive autoreactive lymphocytes as well. This mechanism plays a role only in allo-HCT. e, Tolerization of peripheral autoreactive/alloreactive T cells by regulatory T cells. CD4⁺CD25⁺ regulatory T cells have been implicated in the maintenance of peripheral tolerance to organ-specific self-antigens as well as alloantigens. The secretion of TGF- and IL-10 by regulatory T cells has been suggested to mediate this process. Both allo-HCT and auto-HCT could incorporate this mechanism. f, Tolerization of autoreactive and alloreactive B cells. In addition to alloantigens, haematopoietic chimaerism could potentially tolerize pre-existing recipient B cells to autoantigens expressed by donor haematopoietic cells. This mechanism plays a role only in allo-HCT.