Anti-thymocyte globulin (ATG) is polyclonal, containing Ab specificities capable of binding to various immune-cell subsets implicated in the pathogenesis of GVHD, including T cells, B cells, natural ...killer cells, monocytes/macrophages, neutrophils and DC. We wished to determine which ATG specificities are important for GVHD prevention. We measured day 7 serum levels of 23 ATG specificities in 120 hematopoietic cell transplant recipients whose myeloablative conditioning included 4.5 mg/kg ATG (thymoglobulin). High levels of ATG specificities capable of binding to T- and B-cell subsets were associated with a low likelihood of acute GVHD (aGVHD). High levels of these ATG specificities were associated with increased rates of viral but not bacterial or fungal infections. They were not associated with an increased risk of malignancy relapse; on the contrary, high levels of ATG specificities capable of binding to regulatory T cells and invariant NKT cells were associated with a low risk of relapse. In conclusion, high levels of ATG antibodies to Ag(s) expressed on T and B cells are associated with a low risk of aGVHD and a high risk of viral but not bacterial or fungal infections. These antibodies have neutral or beneficial effects on relapse.
The largest study on post-allogeneic hematopoietic cell transplant lymphoproliferative disorder (PTLD) epidemiology showed a cumulative incidence of 1.7% in patients receiving antithymocyte globulin ...(ATG). We had noted an apparently higher incidence in our transplant recipients whose conditioning included ATG. Therefore, we formally determined the incidence of PTLD through chart review. We also evaluated whether counts of EBV-specific T lymphocytes measured by cytokine flow cytometry could identify patients at risk of developing PTLD. Among 307 allogeneic transplant recipients, 25 (8.1%) developed PTLD. This was biopsy proven in 11 patients, and was fatal in seven patients. Patient age, EBV serostatus, donor type/match or GVHD did not influence PTLD risk significantly. Median onset of PTLD was 55 (range, 28-770) days post transplant. Day 28 EBV-specific T lymphocyte counts were not significantly different in 11 patients who developed PTLD and 31 non-PTLD patients matched for published risk factors for PTLD. In summary, when using conditioning with thymoglobulin 4.5 mg/kg, the incidence of PTLD is relatively high and cannot be predicted by day 28 cytokine flow cytometry-determined EBV-specific T lymphocyte counts. Thus, in this scenario PTLD prevention may be warranted, for example, using EBV DNAemia monitoring with preemptive therapy.
Chronic GVHD (cGVHD) is an important complication of allogeneic hematopoietic cell transplantation (HCT). As preemptive therapy might be efficacious if administered early post transplant, we set out ...to determine whether cGVHD can be predicted from the serum level of a biomarker on day 7 or 28. In a discovery cohort of 153 HCT recipients conditioned with BU, fludarabine and rabbit antithymocyte globulin (ATG), we determined serum levels of B-cell-activating factor, vascular endothelial growth factor, soluble TNF-α receptor 1, soluble IL2 receptor α, IL5, IL6, IL7, IL15, γ-glutamyl transpeptidase, cholinesterase, total protein, urea and ATG. Patients with low levels of IL15 (<30.6 ng/L) on day 7 had 2.7-fold higher likelihood of developing significant cGVHD (needing systemic immunosuppressive therapy) than patients with higher IL15 levels (P<0.001). This was validated in a validation cohort of 105 similarly-treated patients; those with low IL15 levels had 3.7-fold higher likelihood of developing significant cGVHD (P=0.001). Low IL15 was not associated with relapse; it trended to be associated with acute GVHD and was associated with low infection rates. In conclusion, low IL15 levels on day 7 are predictive of cGVHD, and thus could be useful in guiding preemptive therapy.
Infection with murine gammaherpesvirus 68 has become an accepted model for studying the virus/host interactions with regard to gammaherpesvirus infections. Previous studies using gene‐deficient mice ...have revealed that neither IFNγ nor perforin is essential in controlling the outcome of infection or the virus load during chronic infection in C57BL/6 mice. However, pronounced multiorgan fibrosis and splenic atrophy are observed in mice lacking IFNγ or the IFNγ receptor. To study the interplay between perforin and IFNγ in controlling the virus‐induced pathology and the viral load during chronic gammaherpesvirus infection, we infected IFNγ/perforin double‐deficient C57BL/6 mice and followed the course of infection. While absence of perforin prevented the splenic atrophy in IFNγ‐deficient mice, fibrosis did not disappear. Moreover, double‐deficient mice developed extreme splenomegaly, were unable to control the viral load and displayed chronic immune activation. Thus, IFNγ and perforin act in concert to minimize pathology and control the viral load in mice chronically infected with MHV68. Furthermore, while certain aspect of the virus‐induced pathology in IFNγ‐deficient mice may be alleviated in double‐deficient mice, other aspects are exaggerated, and the normal architecture of the spleen is completely destroyed. We believe that these findings add to the understanding of the virus/host interaction during chronic gammaherpes virus infection.
Twelve patients with long-standing symptoms of central nervous system (CNS) dysfunction were found to have elevated antibody titres to human herpesvirus-6 (HHV-6) and Epstein-Barr virus (EBV). All ...patients had four or more of the following neurocognitive symptoms: impaired cognitive functioning, slowed processing speed, sleep disturbance, short-term memory deficit, fatigue and symptoms consistent with depression.
We sought to determine whether elevated antibodies to EBV and HHV-6 indicated chronic viral activation in patients with CNS dysfunction and if their symptoms could be improved by suppressing viral activity with oral valganciclovir.
Patients with high IgG antibody titers against HHV-6 and EBV who were suffering from central nervous system dysfunction and debilitating fatigue for more than one year (median 3 years, range 1–8 years) were treated with 6 months of valganciclovir in an open label study.
Nine out of 12 (75%) patients experienced near resolution of their symptoms, allowing them all to return to the workforce or full time activites. In the nine patients with a symptomatic response to treatment, EBV VCA IgG titers dropped from 1:2560 to 1:640 (
p = 0.008) and HHV-6 IgG titers dropped from a median value of 1:1280 to 1:320 (
p = 0.271). Clinically significant hematological toxicity or serious adverse events were not observed among the 12 patients.
These preliminary clinical and laboratory observations merit additional studies to establish whether this clinical response is mediated by an antiviral effect of the drug, indirectly via immunomodulation or by placebo effect.
PDF
