Contributions
Abstract: EP1771
Type: ePoster
Abstract Category: Therapy - disease modifying - 30 Tools for detecting therapeutic response
Background: Alemtuzumab, a humanized anti-CD52 IgG1 monoclonal antibody, almost completely depletes T and B cells from the circulation. The long-lasting clinical efficacy of alemtuzumab has been associated to unique modifications of the cellular immune network during the re-constitution phase, characterized by the rapid reappearance of Treg lymphocytes and by. prolonged suppression of Th1 and Th17 lymphocytes. However, cases of severely exacerbated central nervous system (CNS) inflammation following alemtuzumab therapy have been described and explained with an exaggerated B-cell activity.
Aim: On the base of these observations, we investigated TFR and TFH cell number and percentage at all the RRMS patients treated with alemtuzumab in our MS Centre.
Results: We observed two alemtuzumab-unresponsive patients that had a severe disease reactivation 4 and 8 months after therapy, respectively. In both patients, we observed the almost complete absence of T follicular regulatory (TFR = CD3+CD4+CD127dimCD25+ CXCR5+PD1+) lymphocytes in the peripheral blood, while T follicular helper (TFH, CD3+CD4+CD127+CD25-CXCR5+PD1+) lymphocytes were detectable. In one case, it was possible to analyse the cerebrospinal fluid lymphocytes. B cells represented the 12.5% of all CSF lymphocytes, 40% were CD20- (while 98% of peripheral blood B-cells were CD20+) and displayed high values of physical parameters, suggesting an active state. Moreover, 48% of CSF B cells expressed high levels of CD38 and 61% (versus 4% of peripheral B cells) expressed the activation marker CD83, suggested to play a role in the germinal centre maturation. Interestingly, the complete absence of TFR was observed in all patients independently of the time-point of sampling. In all the patients, variable percentage of TFH could be demonstrated.
Conclusions: The presence of TFH along with the complete absence of TFR suggests an imbalanced TFH/TFR ratio and, thus, a dysregulated follicular reaction. However, despite the persistent total suppression of TFR the majority of patients benefit from alemtuzumab therapy. Thus the mismatched reconstitution of B and T lymphocytes allows CNS-autoreactive B cell clones to proliferate without control only in a few patients. Whether this phenomenon is related to a given threshold number of circulating TFH or implies the presence of other immunological abnormalities merits to be investigated in a large cohort of patients.
Disclosure: Puthenparampil Marco received travel grant from Novartis, Sanofi-Genzyme, Biogen Idec, Almirall, Teva and Sanofi Aventis and honoraria from Almirall; he has been consultant for Genzyme. Grassivar Francesca, Pantano Giorgia and Plebani Mario have nothing to dislose. Rinaldi Francesca serves as an advisory board member of Biogen-Idec and has received funding for travel and speaker honoraria from Merck Serono, Biogen Idec, Sanofi-Aventis, Teva and Bayer Schering Pharma. Perini Paola has received funding for travel and speaker honoraria from Merck Serono, Biogen Idec, Sanofi-Aventis, and Bayer Schering Pharma and has been consultant for Merck Serono, Biogen Idec and Teva; Gallo Paolo has been a consultant for Bayer Schering, Biogen Idec, Genzyme, Merck Serono and Novartis; has received funding for travel and speaker honoraria from Merck-Serono, Biogen Idec, Sanofi-Aventis, Novartis Pharma and Bayer-Schering Pharma, Teva; has received research support from Bayer, Biogen Idec/Elan, MerkSerono, Genzyme and Teva; and has received research grant from the University of Padova, Veneto Region of Italy, the Italian Association for Multiple Sclerosis, the Italian Ministry of Public Health.
Abstract: EP1771
Type: ePoster
Abstract Category: Therapy - disease modifying - 30 Tools for detecting therapeutic response
Background: Alemtuzumab, a humanized anti-CD52 IgG1 monoclonal antibody, almost completely depletes T and B cells from the circulation. The long-lasting clinical efficacy of alemtuzumab has been associated to unique modifications of the cellular immune network during the re-constitution phase, characterized by the rapid reappearance of Treg lymphocytes and by. prolonged suppression of Th1 and Th17 lymphocytes. However, cases of severely exacerbated central nervous system (CNS) inflammation following alemtuzumab therapy have been described and explained with an exaggerated B-cell activity.
Aim: On the base of these observations, we investigated TFR and TFH cell number and percentage at all the RRMS patients treated with alemtuzumab in our MS Centre.
Results: We observed two alemtuzumab-unresponsive patients that had a severe disease reactivation 4 and 8 months after therapy, respectively. In both patients, we observed the almost complete absence of T follicular regulatory (TFR = CD3+CD4+CD127dimCD25+ CXCR5+PD1+) lymphocytes in the peripheral blood, while T follicular helper (TFH, CD3+CD4+CD127+CD25-CXCR5+PD1+) lymphocytes were detectable. In one case, it was possible to analyse the cerebrospinal fluid lymphocytes. B cells represented the 12.5% of all CSF lymphocytes, 40% were CD20- (while 98% of peripheral blood B-cells were CD20+) and displayed high values of physical parameters, suggesting an active state. Moreover, 48% of CSF B cells expressed high levels of CD38 and 61% (versus 4% of peripheral B cells) expressed the activation marker CD83, suggested to play a role in the germinal centre maturation. Interestingly, the complete absence of TFR was observed in all patients independently of the time-point of sampling. In all the patients, variable percentage of TFH could be demonstrated.
Conclusions: The presence of TFH along with the complete absence of TFR suggests an imbalanced TFH/TFR ratio and, thus, a dysregulated follicular reaction. However, despite the persistent total suppression of TFR the majority of patients benefit from alemtuzumab therapy. Thus the mismatched reconstitution of B and T lymphocytes allows CNS-autoreactive B cell clones to proliferate without control only in a few patients. Whether this phenomenon is related to a given threshold number of circulating TFH or implies the presence of other immunological abnormalities merits to be investigated in a large cohort of patients.
Disclosure: Puthenparampil Marco received travel grant from Novartis, Sanofi-Genzyme, Biogen Idec, Almirall, Teva and Sanofi Aventis and honoraria from Almirall; he has been consultant for Genzyme. Grassivar Francesca, Pantano Giorgia and Plebani Mario have nothing to dislose. Rinaldi Francesca serves as an advisory board member of Biogen-Idec and has received funding for travel and speaker honoraria from Merck Serono, Biogen Idec, Sanofi-Aventis, Teva and Bayer Schering Pharma. Perini Paola has received funding for travel and speaker honoraria from Merck Serono, Biogen Idec, Sanofi-Aventis, and Bayer Schering Pharma and has been consultant for Merck Serono, Biogen Idec and Teva; Gallo Paolo has been a consultant for Bayer Schering, Biogen Idec, Genzyme, Merck Serono and Novartis; has received funding for travel and speaker honoraria from Merck-Serono, Biogen Idec, Sanofi-Aventis, Novartis Pharma and Bayer-Schering Pharma, Teva; has received research support from Bayer, Biogen Idec/Elan, MerkSerono, Genzyme and Teva; and has received research grant from the University of Padova, Veneto Region of Italy, the Italian Association for Multiple Sclerosis, the Italian Ministry of Public Health.