Profound Depletion of Host Conventional Dendritic Cells, Plasmacytoid Dendritic Cells, and B Cells Does Not Prevent Graft-versus-Host Disease Induction

Abstract

The efficacy of alloSCT is limited by graft-versus-host disease (GVHD). Host hematopoietic antigen presenting cells (APCs) are important initiators of GVHD making them logical targets for GVHD prevention. Conventional dendritic cells (cDCs) are key APCs for T cell responses in other models of T cell immunity and they are sufficient for GVHD induction. However, we report here in two polyclonal GVHD models in which host hematopoietic APCs are essential, that GVHD was not decreased when recipient cDCs were inducibly or constitutively deleted. Additional profound depletion of plasmacytoid DCs and B cells, with or without partial depletion of CD11b+ cells, also did not ameliorate GVHD. These data indicate that, in contrast to pathogen models, there is a surprising redundancy as to which host cells can initiate GVHD. Alternatively, very low numbers of targeted APCs were sufficient. We hypothesize the difference in APC requirements in pathogen and GVHD models relates to the availability of target antigens. In anti-pathogen responses specialized APCs are uniquely equipped to acquire and present exogenous antigens whereas in GVHD all host cells directly present alloantigens. These studies make it unlikely that reagent-based host APC depletion will prevent GVHD in the clinic.

Autologous apoptotic cells preceding transplantation enhance survival in lethal murine graft-versus-host models

“…Shlomchik et al recently demonstrated that selective depletion of host DCs did not ameliorate GVHD. 42 It has been shown that uptake of apoptotic cells by DCs induces Tregs, which when triggered by specific antigens, can act back via a "feedback loop" on immature DCs to further block the upregulation of costimulatory molecules. Additionally, Tregs are able to directly inhibit T-cell activation by inhibition of CD28 signaling.…”

Siglec-G–CD24 axis controls the severity of graft-versus-host disease in mice

“…36,37 Recent data have indicated that both host hematopoietic or nonhematopoietic APCs, in the absence of one or another, can activate donor T cells and induce GVHD. 18,19,21 Furthermore, the elimination of specific hematopoietic APC subsets, such as DCs or macrophages, may aggravate GVHD, suggesting that these cells may play a role in controlling GVHD. 18,20,22,44 These observations, taken in light of our data, suggest that the negative regulatory pathways of professional APCs, DCs, or macrophages, might be critical for reducing GVHD severity following its induction by the activation of donor T cells by the DAMP/PAMP activated host APCs.…”

“…This is particularly critical in light of the recent observations, which demonstrate that the absence of any one subset of professional host-derived hematopoietic APCs, such as DCs or macrophages, contrary to the expectations of reducing donor T-cell responses, are either irrelevant, or actually enhance donor T-cell responses and accentuate GVHD severity. [18][19][20][21][22] These newer observations suggest that pathways that mitigate the hematopoietic APCs may be as critical for attenuating GVHD.…”

Siglec-G represses DAMP-mediated effects on T cells

“…CD24 is broadly expressed in hematopoietically derived cells, immature neuronal cells, and epithelial cells (26). Given the complexity and number of cell types involved in inducing and amplifying GVHD, whether Siglec expression on donor or host B cells or other cells will affect acute GVHD remains to be explored (27,28).…”