The data presented here suggest that higher IL-7 levels produced in response to T-cell depletion before therapy may activate thymic rebound in adult HIV-infected patients under HAART.
Thymic tissue measurement is now an accepted biological marker for thymus function . We have recently reported an increase in thymic function, measuring thymic volume, as early as 12 weeks after HAART in HIV-infected patients. Also, a direct correlation between thymic volume and TREC- bearing cells and an inverse correlation between thymic volume and age has been found, supporting the reliability of the technique for measuring the thymus . We have also reported that thymic volume was an independent predictor for CD4 T-cell repopulation in HIV-infected adults under HAART .
The role of IL-7 in T-cell homeostasis in response to T-cell depletion has not been found for other cytokines and soluble factors [19,21,22]. In animal models, it has been shown that IL-7 enhances the peripheral expansion of mature T cells , and preferentially thymic-dependent pathways in T-cell generation after T-cell depletion . Recent studies have shown that the administration of exogenous IL-7 to in-vitro systems and mice increased the number of TREC-bearing cells produced by the thymus . These observations and others [28,29] strongly suggest an important role of this cytokine in the regeneration of T cells by the thymus, at least in murine models.
The inverse correlation between IL-7 levels and total CD4 T cells before therapy supports the important role of IL-7 in response to T-cell depletion. This is the first study in which an inverse correlation between IL-7 levels and thymic volume before therapy was observed. Consequently, IL-7 seems not to be necessarily produced in the thymus, but probably in the periphery. Patients with an absence of a radiological image of the thymus thus had higher levels of IL-7. These data support findings previously reported, in which IL-7 in untreated patients should preferentially be produced by peripheral lymphoid organs in response to T-cell depletion .
A significant decrease in IL-7 levels during follow-up compared with baseline levels was observed, probably in response to the significant increase in total CD4 T-cells during follow-up. These results suggest that the homeostatic response is fast and sensitive in HIV replication control after HAART. The increase in thymic function-associated parameters and the stability in the memory T-cell subset during follow-up suggest that repopulation of HIV-infected adults under HAART is preferentially led by the thymus, at least in the first 12 weeks of follow-up. We speculate that the difference between naive and memory T cells during follow up could be explained partly by the different mechanisms of homeostatic cell proliferation. Naive T cells proliferate relatively slowly and depend on the contact of self-major histocompatibility complex and peptide ligands. In T-cell depletion conditions, when the total number of naive T cells decreases below a certain level, IL-7 is increased because of a reduction in the number of T-cell receptors and MHC–peptide interactions . The fast MHC-independent homeostatic regulation of memory T cells could perhaps explain why IL-7 seems not to be involved in their expansion.
The IL-7 level was the only variable associated with changes in thymic volume by multiple linear regression analysis during the follow-up. These data strongly suggest that a baseline IL-7 level is a factor that might trigger thymic rebound in HIV-infected adults under HAART. Two conditions have to be considered, that there is no irreversible damage of the thymus and no irreversible damage of the peripheral lymphoid organs. No parameter was independently associated with changes in either naive T cells or TREC-bearing cells at each timepoint compared with the baseline. This fact could be explained because the naive T-cell number is not a true thymic-related marker in HIV infection. Therefore, a naive T-cell increase could be caused by peripheral expansion after HAART [30,31]. The small number of patients could explain the absence of a correlation between IL-7 levels and changes in TREC-bearing cell counts during follow-up. Also, it might be possible that thymic volume measurement could be more reliable and a better tool for the determination of thymic function compared with TREC-bearing cell determination .
In our opinion, IL-7 should not be considered to be an immunomodulatory therapy, at least in HIV infection, because patients with irreversible damage to the thymus can not produce new T cells independently of the levels of IL-7. Moreover, the administration of IL-7 in order to increase T-cell counts is also discouraged, because this cytokine has been shown to enhance HIV replication [22,32–34]. HIV infection could thus be considered a ‘soil immunodeficiency’ and not a ‘signal immunodeficiency'. Nevertheless, the potential use of IL-7 as a therapy in other types of immunocompromised patients might be indicated.
In summary, our data show for the first time in humans that IL-7 might be involved in the activation of increased thymic volume after T-cell depletion, and specifically in adult HIV-infected patients undergoing HAART. The absence of a radiological image of the thymus in some patients with higher levels of IL-7 also supports the theory that IL-7 is mainly produced in peripheral organs in untreated patients. New soluble factors involved in the modification of thymic function in patients under HAART and new therapeutic strategies in order to improve immune reconstitution in these patients are under research.
The authors would like to thank the individuals who participated in this study, as well as M. Olivera and A. Gayoso for excellent technical assistance.
Sponsorship: This work was supported by research grants from the Fondo para la Investigación y Prevención del SIDA en España (FIPSE 2132/00 and FIPSE 12304/02) integrated by the Ministerio de Sanidad y Consumo, Abbott Laboratories, Boehringer Ingelgeim, Bristol Myers Squibb, GlaxoSmithKline, Merck Sharp and Dohme and Roche, Fondo de Investigaciones Sanitarias (FIS 00/0521), and by the kind support of Fundación Wellcome, España. This work was also partially supported by Red de Investigación en SIDA (RIS) by Ministerio de Sanidad y Consumo (SPAIN).
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