CD8-Predominant T Cell Meningitis Accompanies Gvhd in Primates and Is Prevented with Immunoprophylaxis

Graft versus host disease (GvHD) is an often fatal complication of allogeneic tissue transplantation.  While typical targets of GvHD include the skin, lung, liver and GI tract, a myriad of other organ systems are being identified as targets of this disease.  Although the neurologic complications that occur during hematopoietic stem cell transplant (HCT) have been extensively described (Siegal et al., BBMT, 2007), little information is available about the incidence and biology of GvHD in the central nervous system (CNS).  Case reports have shown that the CNS can be a target of GvHD and show high mortality rates when involved (Saad et al., JCO, 2009). A recent study found both pathologic and behavioral consequences of CNS-GVHD in a mouse model (Hartrampf et al., Blood, 2013).  Further study of CNS-GvHD is needed to better understand this entity that is often difficult to access clinically.

Non-human primates have been shown to closely model humans during and after HCT.  To investigate the prevalence of CNS manifestations of acute GvHD such a model, we conducted a HCT study with the following Transplant/GvHD prophylaxis regimens: 1) Autologous/None 2) Allogeneic/None 3) Allogeneic/Tacrolimus & Methotrexate 4) Allogeneic/Rapamycin.  Immunohistochemistry performed on the CNS meninges of untreated HCT recipients with severe GvHD demonstrated a CD3+, CD20- meningeal lymphocytic infiltration, which was not observed in autologous transplants (Figure 1) and which was accompanied by significant behavioral abnormalities and neurologic compromise.  The number of CD8+ cells found in these infiltrates was significantly higher in animals with GvHD than in either controls or in animals treated with Tac/Mtx or Rapamycin prophylaxis.  CNS-infiltrating cells demonstrated higher expression of granzyme B (Figure 1) and Ki-67 (not shown), which is consistent with previous characterization of the CD8+ functional status during acute GvHD in a non-human primate model (Miller et al., Blood, 2010). Importantly, our results show that LFA-1 expression is highly upregulated in CNS leukocyte infiltrates of animals with untreated GvHD (Figure 2). LFA-1 is an integrin that is critical for leukocyte trafficking into the CNS during demyelinating disease (Hu et al., J Leuk Bio, 2010).  These results suggest that the mechanisms of T cell infiltration into the CNS during GVHD may have important similarities to autoimmune-mediated CNS diseases such as multiple sclerosis, and thus may be amenable to targeted therapies such as integrin-blockade.

Our findings argue that CNS-GvHD can occur in primates undergoing HCT, and is characterized by an infiltrate of activated, integrin-expressing CD8 T cells. These results underscore the importance of including GVHD in the differential diagnosis of CNS symptoms after HCT, and suggest that targeted therapeutic strategies may be able to address this often under-recognized complication of HCT.