Subclinical GvHD in non-irradiated F1 hybrids: severe lymphoid-tissue GvHD causing prolonged immune dysfunction

Abstract

GvHD is an important complication of allogeneic hematopoietic SCT. Parent-in-F1 models are frequently used to study GvHD immunobiology; the characteristics of parent-in-F1 GvHD vary between strain combinations and induction protocols. Here, we observed that a high-dose challenge of non-irradiated B6DBA2F1 and B6SJLF1 recipients with C57BL/6 splenocytes left the majority of recipients clinically healthy, while inducing progressive high-grade donor T-cell chimerism. We investigated this previously undescribed pattern of parent-in-F1 T-cell alloreactivity and studied the effect of serial parental splenocyte infusions on epithelial and lymphohematopoietic tissues. The majority of recipients of 4 weekly splenocyte infusions showed long-term survival with gradual establishment of high-grade donor chimerism and without any signs of epithelial-tissue GvHD. A minority of recipients showed BM failure type of GvHD and, respectively, graft rejection. Moreover, long-term F1 chimeras showed protracted pancytopenia, and in peripheral lymphoid tissues severe lymphopenia and near-complete eradication of APCs and dysfunction in antigen-presenting capacity in remaining APC. Hematopoiesis and lymphoid tissue composition recovered only after multilineage donor chimerism had established. In conclusion, we report on a novel type of parent-in-F1 hybrid GvHD, where a cumulative high dose of C57BL/6 parental splenocytes in non-irradiated F1 mice induces subclinical but severe hematolymphoid-tissue GvHD, causing prolonged immuno-incompetence.

Models of Lung Transplant Research: a consensus statement from the National Heart, Lung, and Blood Institute workshop

“…A similar strategy has been previously employed in the field of bone marrow transplantation to study chronic graftversus-host disease (GVHD) with injection of parental cells into F1 recipients or complete MHC mismatch (121)(122)(123)(124)(125)(126). These studies demonstrate how the interplay between local innate immunity and alloreactive T cell subsets and alloantibody deposition contribute to chronic pulmonary GVHD with fibrotic (including OB-like) pathology.…”

Subset characterization of myeloid-derived suppressor cells arising during induction of BM chimerism in mice

“…18 More recently, we documented a similar expansion of CD11b þ Gr1 þ myeloid progenitor cells in two parent-in-F1 models of chimerism induction. 19 In fact, we showed that a cumulative high-dose challenge with parental C57BL/6 splenocytes in non-irradiated B6DBAF1 and B6SJLF1 recipients induced a state of high-grade multilineage donor chimerism, associated with a transient expansion of CD11b þ Gr-1 þ myeloid progenitor cells. In both these parent-in-F1 and radiation chimeras, challenge with non-tolerant donor T cells (DLI-inoculum) mediated strong LH-GvH reactivity and an anti-tumor response, whereas fatal BM failure-type or epithelial-type GVHD was not seen.…”

“…19 In this model, non-irradiated B6DBA2F1 recipients were given four i.v. challenges with 25 Â 10 6 C57BL/6 splenocytes each separated by 1 week (day 0, 7, 14 and 21).…”

“…16,17 Interestingly, studies in mice have shown that myeloid progenitor cells with suppressive capacity can expand as a physiological bystander phenomenon in the course of BM chimerism induction, suggesting a potential regulating role in the post-transplant immune environment. 18,19 GVHD still is a major complication of allogeneic hematopoietic SCT (allo-HSCT) in the treatment of various hematological malignancies and often occurs in close association with immune-mediated antitumor responses (GVL). 20 Both GVHD and GVL are known to principally depend on the reactivity of donor T cells against host Ags.…”

“…Hypothesizing that such regulatory myeloid cells, arising after the transplant, may regulate post-transplant T-cell alloreactivity, here we aimed to characterize this expanding myeloid cell population in more detail. Specifically, we used the previously published parent-in-F1 model 19 to document the existence of phenotypical and/or functional MDSC subsets, to document the in vitro and in vivo immune suppressive behavior of these defined subsets, and lastly, we aimed to document whether T-cell alloreactivity can lead to activation of MDSC in the post-transplant period in vivo.…”