We propose a phase II study of alemtuzumab for the treatment of steroid-refractory acute graft-vs.-host disease in recipients of allogeneic hematopoietic stem cell allografts. Moderate to severe acute GvHD (grades II-IV) occurs in 30-50% of matched related recipients and 50-70% of unrelated recipients of unmodified allografts, despite standard prophylaxis. Acute GvHD can also occur after T cell-depleted allografts, especially from HLA-mismatched and/or unrelated donors. Grade II-IV GvHD requires systemic therapy, typically high dose parenteral steroids. Approximately 60% of these patient prove steroid refractory, however, and require alternative therapy for which there are no standard, effective options. We have recently identified selective expression of CD52, which is targeted by alemtuzumab, by different subtypes of human dendritic cells (DCs). Monocyte-derived DCs (moDCs) express CD52, whereas Langerhans cells (LCs) and dermalinterstitial DCs (DDC-IDCs) never express this epitope, either as resident populations in normal or inflamed tissue, or as cytokine generated progeny of CD34+ HPCs in vitro. Although alemtuzumab given pretransplant eliminates host moDCs without impairing engraftment of donor moDCs, the effect of alemtuzumab given after transplant on donor moDCs is not known. MoDCs are the most highly phagocytic DCs and thereby most capable of taking up host Ags from dying cells for cross-presentation to engrafting donor T cells. The beneficial effect of antJ-CD52 therapy on GvHD may therefore derive not only from its depletion of alloactivated T cells but also from the selective elimination of moDCs from the inflammatory environment of GvHD. The preservation of LCs and DDC-IDCs after anti-CD52 treatment may allow these DCs to play formative roles in the redevelopment of acquired and beneficial immunity. This is distinct from the outcome after daclizumab (anti-CD25) or thymoglobulin/ATG therapy, both of which nonselectivelv target most or all monocytes and DCs. as well as T cells. We propose that GvHD is separable from graft-host tolerance, reconstitution of cellular immunity, and GvT benefits of allogeneic HSCT, all at the level of antigen-presentation by DCs. We will (1) determine the efficacy of alemtuzumab to achieve responses in steroid-refractory acute GvHD by its selective targeting of moDCs as well as T cells: (2) assess whether alemtuzumab exerts a steroid-sparing effect, obviates the need for other salvage therapies, lessens the incidence of chronic GvHD, and improves OS and DFS; and (3) quantify circulating levels of inflammatory cytokines in GvHD sera/plasma that may in turn support DC activation and stimulation of donor T cells against host alloantigens; and enumerate changes in circulating NK, NKT, and T-reg cells, as well as circulating and tissue-resident CD52 pos/neg DC populations. We predict that alemtuzumab will effectively manage steroid-refractory acute GvHD, preserving freedom from relapse and allowing immune reconstitution to proceed more normally in the absence of continued immune suppression by high dose steroids.
| Rossi, Marco; Young, James W (2005) Human dendritic cells: potent antigen-presenting cells at the crossroads of innate and adaptive immunity. J Immunol 175:1373-81 |
