Low T-Cell Responses to Mitogen Stimulation Predicts Poor Survival in Recipients of Allogeneic Hematopoietic Stem Cell Transplantation

Abstract

BackgroundSuccessful engraftment and reconstitution of the innate and adaptive immune system are associated with improved outcomes in recipients of allogeneic hematopoietic stem cell transplantation (HSCT). A clinically meaningful and simple biomarker of immunosuppression could potentially assist clinicians in their decision-making. We aimed to determine the relationship between T-cell production of interferon gamma (IFN-γ) in response to phytohemagglutinin (PHA) to clinical outcomes in HSCT recipients.MethodsA prospective observational multicenter study of 73 adult allogeneic HSCT recipients was conducted in Melbourne, Australia. Eligible participants were >18 years and at risk of cytomegalovirus disease. T-cell responses to PHA were assessed at 3, 6, 9, and 12 months post-HSCT using the commercial quantiferon-cytomegalovirus assay, which quantifies IFN-γ production by ELISA following stimulation with PHA. A low response was defined as IFN-γ <0.5 IU/ml following stimulation with PHA.ResultsAt 3 months post-HSCT, high responses to PHA (median IFN-γ 7.68 IU/ml) were seen in 63% of participants and low responses to PHA (median IFN-γ 0.06 IU/ml) in 37%. IFN-γ responses to PHA were significantly associated with the severity of acute graft versus host disease (AGVHD) (spearman r = −0.53, p < 0.001) and correlated with blood lymphocyte count (spearman r = 0.52, p < 0.001). Twelve month overall survival was greater in individuals with high compared to low IFN-γ response to PHA at 3 months [92 vs. 62%, respectively, Cox proportional hazard ratio (HR): 4.12 95% CI: 1.2–13.7, p = 0.02]. Non-relapse mortality (NRM) was higher in individuals with low IFN-γ response to PHA (competing risk regression HR 11.6 p = 0.02). In individuals with no AGVHD compared to AGVHD and high IFN-γ response to PHA compared to AGVHD and low IFN-γ response to PHA, 12-month survival was 100 vs. 80 vs. 52%, respectively (log rank test p < 0.0001).ConclusionLow IFN-γ response to PHA at the 3-month time-point following allogeneic HSCT was predictive of reduced 12-month overall survival, increased NRM, and reduced survival in recipients with AGVHD. Assessing IFN-γ response to PHA post-HSCT may be a clinically useful immune biomarker.

CMV-Specific Immune Response—New Patients, New Insight: Central Role of Specific IgG during Infancy and Long-Lasting Immune Deficiency after Allogenic Stem Cell Transplantation

“…Knowing that a low IFN-γ response to phytohemagglutinin (PHA) predicts poor survival [11], I assessed CMV-specific and mitogen-induced IFN-γ release using the same commercial quantiferon-cytomegalovirus assay. Unfortunately, in the quantiferon technique, the interferon immune response after CMV-peptide-laden human leukocyte antigen (HLA) class I stimulation showed higher level than PHA-induced in the first wave of lymphocyte reconstitution (i.e., between 2–11 and 19–01), which of note, was during most intensive CMV reactivation [12].…”

“…Previous studies in both solid and stem cell transplant recipients reported that the Quantiferon assay was frequently (up to 38%) “indeterminate” because of a poor mitogen response as a result of immunosuppression [11,13,14]. In this context, for precise interpretation of the quantiferon assay the cytometric analysis, blood count and cyclosporine (CsA) level were performed from the same blood collection (the same venipuncture) and is presented in Figure 1.…”

“…PHA pan-T-cell mitogen and stimulator did not act when severe T-cell lymphopenia was observed and the patient’s blood contained T cell immunosuppressants (here ATG and CsA) (Figure 1). On the contrary, no association was seen between the PHA-induced quantiferon response and ATG regimen [11], but such a statistical analysis was done at 3 months. Likewise, in my observation at 3 months (i.e., 2–11), full chimerism was observed, the PHA-induced quantiferon result was lower than CMV-induced, but a CD16+ 56+ NK cells increase was observed before T cell reconstitution (Figure 1).…”

“…IFNγ release under the influence of CMV epitopic peptides quantiFERON-CMV assay (QIAGEN) (named here as quantiferon) was used for cellular immune response monitoring [11,21,31]. According to the manufacturer’s details, quantiferon is an in vitro assay using a peptide cocktail to stimulate cells in heparinized whole blood (cat.…”

A Targeted Screening Program for Latent Tuberculosis Infection Among Hematopoietic Cell Transplant Recipients

“…We found that an indeterminate QFT was associated with worse posttransplant survival. Others have shown that HCT recipients and other cancer populations with poor mitogen responses post-HCT are associated with poor outcomes [ 37 , 38 ]. Although intriguing, additional immunologic assessments, disease associations, and evaluation of other confounders need to be considered before considering the QFT mitogen response as a predictor for posttransplant outcomes.…”