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Abstract: E1400

Type: Eposter Presentation

Background
Treatment of HIV⁺ lymphoma patients has been greatly improved by the combination of highly active antiretroviral therapy with high-dose chemotherapy and autologous stem cell transplantation (ASCT). It has been demonstrated that the T-cell recovery after ASCT does not differ between HIV⁺ and HIV^- patients with non-Hodgkin lymphoma (NHL), because the two groups present with a similar thymic output, as measured by means of T-cell receptor excision circles (TRECs) quantification. Nevertheless, whether T-cell repertoire (TCR) modifications may occur at the same extent in the two group of patients receiving ASCT has not been described yet.

Aims
To better elucidate the extent of T-cell recovery and its effects on the TCR repertoire in HIV⁺ and HIV^- patients with NHL who underwent ASCT.

Methods
Eleven ASCT-treated HIV⁺ and nine HIV^- NHL patients were followed for 2 years (T0: pre-ASCT; T6, T12 and T24: 6, 12 and 24 months from ASCT, respectively). The number of TRECs was measured by quantitative real-time PCR. Recent T emigrants (RTE), the cells that were recently produced in the thymus, were identified as CD4⁺CD45RA⁺CCR7⁺ lymphocytes expressing the CD31 molecule. The analysis of TCR beta variable (TCRBV) families was performed by complementarity determining region 3 (CDR3) spectratyping. The deviation of CDR3 size distributions from a theoretical Gaussian curve in each TCRBV family was analysed both qualitatively and quantitatively using the generalized Hamming distance method. Results were compared to that of age matched healthy controls (HC).

Results
Starting at T6, both HIV⁺ and HIV^- patients presented with a gradual but significant increase in naïve CD4 lymphocytes (difference between means: T12 − T6 = 27 cells/ml, p = 0.011), RTE (T12 − T6 = 23 cells/ml, p = 0.003) and TRECs⁺ cells (T12 − T0 = 1355 TRECs/ml, p < 0.001) that reached the top at T24. TCR repertoire analysis showed that, compared to HC, the mean proportion of TCRBV families with shifted, restricted and mono/oligoclonal profiles of TCRBV families was significantly higher in samples obtained pre-ASCT (HIV⁺ − HC = 32.3%, p < 0.001; HIV^- − HC = 39.8%, p < 0.001) and post-ASCT (HIV⁺ − HC = 29.8%, p = 0.002; HIV^- − HC = 24.2%, p = 0.012) in both groups of patients. Quantitative analysis showed that the mean perturbation of CDR3 distributions was higher compared to HC in infected and uninfected patients both pre-ASCT (HIV⁺ − HC = 10.5%, p < 0.001; HIV^- − HC = 12.8%, p = 0.001) and post-ASCT (HIV⁺ − HC = 13.1%, p < 0.001; HIV^- − HC = 12.6%, p < 0.001). However, in both HIV⁺ and HIV^- patients, the pattern of TCR repertoire distortions changed 24 months after ASCT, as supported by modifications in the number of perturbed TCRBV and within the CDR3 distribution profiles, leading to either enlargement or restriction of the TCR heterogeneity.

Conclusion
Using different approaches, we confirmed that new CD4⁺ cell production is similarly increased in HIV⁺ and HIV^- patients with NHL that received ASCT. The production of new lymphocytes was not sufficient to induce a general enlargement of the TCR repertoire but, nevertheless, led to relevant modifications of TCRBV family profiles, not related to HIV infection. Because TCR repertoire is usually extremely stable in HC, these modifications cannot be merely due to a physiologic repertoire “drift” over time, but are likely due to a repertoire re-assortment occurring after ASCT. Modulation of TCR repertoire may have important implications for immune system-mediated anti-infective and anti-tumor activities.

Session topic: E-poster

Keyword(s): Autologous hematopoietic stem cell transplantation, HIV related lymphoma, Immune reconstitution, T cell repertoire