Possible Role of Minor H Antigens in the Persistence of Donor Chimerism after Stem Cell Transplantation; Relevance for Sustained Leukemia Remission

Abstract

Persistent complete donor chimerism is an important clinical indicator for remissions of hematological malignancies after HLA-matched allogeneic stem cell transplantation (SCT). However, the mechanisms mediating the persistence of complete donor chimerism are poorly understood. The frequent coincidence of complete donor chimerism with graft-versus-leukemia effects and graft-versus-host disease suggests that immune responses against minor histocompatibility antigens (mHags) are playing an important role in suppressing the host hematopoiesis after allogeneic SCT. Here, we investigated a possible relationship between donor immune responses against the hematopoiesis-restricted mHag HA-1 and the long-term kinetics of host hematopoietic chimerism in a cohort of 10 patients after allogeneic HLA-matched, HA-1 mismatched SCT. Functional HA-1 specific CTLs (HA-1 CTLs) were detectable in 6/10 patients lysing host-type hematopoietic cells in vitro. Presence of HA-1 CTLs in the peripheral blood coincided with low host hematopoiesis levels quantified by highly sensitive mHag specific PCR. Additionally, co-incubation of host type CD34+ cells with HA-1 CTLs isolated after allogeneic SCT prevented progenitor and cobblestone area forming cell growth in vitro and human hematopoietic engraftment in immunodeficient mice. Conversely, absence or loss of HA-1 CTLs mostly coincided with high host hematopoiesis levels and/or relapse. In summary, in this first study, presence of HA-1 CTLs paralleled low host hematopoiesis levels. This coincidence might be supported by the capacity of HA-1 CTLs isolated after allogeneic SCT to specifically eliminate host type hematopoietic stem/progenitor cells. Additional studies involving multiple mismatched mHags in more patients are required to confirm this novel characteristic of mHag CTLs as factor for the persistence of complete donor chimerism and leukemia remission after allogeneic SCT.

Possible Impact of Cytomegalovirus-Specific CD8+ T Cells on Immune Reconstitution and Conversion to Complete Donor Chimerism after Allogeneic Stem Cell Transplantation

“…We propose that recognition of CMV antigens on host endo-or epithelial cells [56,60] or on host antigen-presenting cells [61,62] by donor-derived CMV-CTLs may induce the release of proinflammatory cytokines [63,64] (such as IFN-γ and tumor necrosis factor-α), leading to an upregulation of HLA and host minor histocompatibility antigens on host tissues [65][66][67][68]. Enhanced presentation of allo-antigens on endo-or epithelial cells or on host antigen-presenting cells may boost the expansion of alloreactive donor T cells finally mediating the elimination of the residual host hematopoiesis [9]. Future studies are required to demonstrate the proposed association between the emergence of CMV-CTLs and minor histocompatibility antigen CTLs [9].…”

“…As previously shown, both extent and speed of the overall T cell reconstitution were closely related to the presence of CMV-CTLs. Because donor T cells are the driving force for the conversion to complete donor chimerism [9], host chimerism was analyzed separately in CMV R+/D-and R+/D+ patients at 3 months after allo-SCT in relation to the presence or absence of CMV-CTLs.…”

“…Moreover, enhanced T cell reconstitution is strongly linked to GVHD [8]. Minor histocompatibility antigens mismatched in the patient direction are direct targets of the allo-immune response mediating the elimination of the host hematopoiesis after allo-SCT [9]. However, the exact mechanisms driving the allo-immune responses after allo-SCT are still unknown.…”

Human CD8+ CD57- TEMRA cells: Too young to be called "old"

“…viral infections [1] or transplantation antigens [2]. Particularly, end-stage differentiation of antigen-specific CD8+ T-cells may precede loss of immune responses.…”

Minor Antigen Disparities Impede Induction of Long Lasting Chimerism and Tolerance through Bone Marrow Transplantation with Costimulation Blockade

“…In the human setting, disparities in mHAg increase not only the rates of rejection and graft-versus-host-disease (GVHD) [11] but also the efficacy of graft-versus-leukemia-effects (GVL) [12]. Recently, mHAg have also been reported to play an essential role in the persistence of donor chimerism [13]. …”