Acid sphingomyelinase deficiency does not protect from graft-versus-host disease in transplant recipients with Niemann-Pick disease

To the editor:

Rotolo et al reported¹  that ceramide, generated from sphingomyelin by acid sphingomyelinase (ASM) and coalesced into plasma membrane platforms, is necessary for transmembrane relay of cytotoxic T-lymphocyte (CTL) signals, such as Fas-FasL signals, critical in the effector stage of acute graft-versus-host disease (GVHD). Due to defective CTL-mediated lysis of ASM-deficient organs, recipients had reduced GVHD lethality and target organ injury, especially of the gastrointestinal tract and liver. In addition, GVHD amelioration was also associated with increased donor T-cell apoptosis and reduced proinflammatory cytokine responses.

To determine whether the effects of ASM deficiency in mice were translatable to humans, we examined the incidence of acute and chronic GVHD in patients with ASM deficiency, termed Niemann-Pick (NP) disease. Approval was obtained from the University of Minnesota's Institutional Review Board for these studies. Informed consent was provided according to the Declaration of Helsinki. At least 4 types of NP disease exist, 2 of which have either complete (neurovisceral form, NP type A, or NPA) or partial (visceral form, NP type B, or NPB) constitutional deficiency of ASM.²  In both NPA and NPB, ASM substrate (sphingomyelin) accumulates to the same degree in viscera, and leads to progressive multiorgan dysfunction and death. Because phenotypic cross-correction is feasible in ASM-deficient mice,³  hematopoietic cell transplantation (HCT) has been proposed as a therapy for both forms.

Based on published reports^4-9  and data from the Center for International Blood and Marrow Transplantation Research, 24 NP disease patients who received allogeneic HCT from 1986 to 2007 were available for analysis (Table 1). The median age at HCT was 2 years (range, 0.6-10 years), and median follow-up was 4 years (range, 1-17 years). Nine patients developed GVHD (6 acute and 3 chronic GVHD), and 2 patients had both acute and chronic forms of GVHD. Acute GVHD involved skin in all cases (2 patients with grade 1 GVHD, 1 patient with grade 2 GVHD, and 3 patients with grade 3 GVHD; Glucksberg score), gastrointestinal tract in 3 patients (1 patient with grade 1 GVHD and 2 patients with grade 2 GVHD), and liver in 4 patients (2 patients with grade 1 GVHD, 1 patient with grade 2 GVHD, and one patient with grade 3 GVHD). Chronic GVHD was limited in 2 patients and extensive in one.

We found that patients with NP disease had incidence and severity of GVHD comparable with other patients with inborn errors of metabolism (IEM) undergoing transplantation during the same period (Table 1). The expected incidence of clinical GVHD after allogeneic transplantation in a pediatric population with IEM is 34% for acute GVHD and 16% for chronic GVHD, not significantly different from that for NP patients. Therefore, the magnitude of any inhibitory effect of ASM deficiency at the level of GVHD target organs may have been circumvented by the donor T-cell numbers infused, the conditioning regimen type or intensity, the GVHD prophylactic drugs used, host environmental factors, nature or degree of the proinflammatory response, or species-specific GVHD pathophysiologic mechanisms.¹⁰  Given the available data, we find no evidence that NP patients are spared from GVHD target organ injury or that ASM modulates GVHD pathology in humans.