Interleukin-7 Treatment Research Articles

Effects of human interleukin 7 on HIV-1 replication in monocyte-derived human macrophages

Interleukin 7 (IL-7) contributes to development and proliferation of T cells. We investigated the effect of IL-7 on HIV-1 infected monocyte-derived human macrophages. IL-7 treatment of macrophages at a concentration of 10 ng/ml reduced replication of the R5 HIV-1 strain by approximately 50%. Meanwhile, HIV-1-infected macrophages themselves could excrete approximately 20% more IL-7 than uninfected macrophages. These results suggest that IL-7 could be used as a therapeutic modality to recover CD4 T cells.

T cell development, ageing and Interleukin-7

Interleukin-7 (IL-7) is a cytokine with a central role in the development and maintenance of the peripheral T cell pool. In the mouse, expression of the IL-7 gene in the thymus has been carefully followed from gestation onwards throughout the lifespan. One of the features of its expression in the thymus is that it changes with time, declining measurably as the animal ages. This reduction is associated with a decrease in thymic size, cellularity and output. Analysis of transgenic animals carrying either IL-7 or IL-7 receptor transgenes reveals that the intrathymic level of IL-7 has a critical effect on the production of T cells, and that this may not be a linear relationship. This is an important consideration for therapy involving treatment of old animals with IL-7 of which there are reports indicating some rejuvenation of the thymus following IL-7 treatment, which is never complete. The thymus does not appear to return to the size and cellularity seen in youth. Several possible scenarios could account for this, including the inability to maintain IL-7 within defined limits in the thymus during the therapy.

Clade-specific differences in active viral replication and compartmentalization.

This review focuses on the impact of HIV-1 clade-specific polymorphisms on the dynamics of viral replication and compartmentalization in vivo. HIV-1 transcription and compartmentalization are essentially modulated by interconnected parameters: cellular activation by T-cell receptor engagement or cytokine signalling in different tissues, and viral polymorphisms in the long terminal repeat and Tat protein. Moreover, the gut-associated lymphoid tissue plays a central role in HIV-1 pathogenesis. It selectively supports viral replication in primary infection and may influence viral quasispeciation during interleukin-7 treatment. In addition, interleukin-7, permanently released by the intestinal epithelial cells, preferentially activates the HIV-1 clade C promoter versus the B and E counterparts. In view of the influence of long terminal repeat polymorphisms on the replication of different clades and the importance of HIV-1 replication in the gut-associated lymphoid tissue during primary infection, it will be important to show whether the amplitude and speed of gut-associated lymphoid tissue depletion in primary infection are also clade dependent and can impact disease progression. In the context of therapeutic interleukin-7 treatment, this cytokine might well foster growth of HIV-1 clade C and perhaps clade A viruses. This needs attention.

IL-7 Blockade Prevents Graft-Versus-Host Disease and Improves T Cell Reconstitution Following Allogeneic Bone Marrow Transplantation.

Interleukin 7 (IL-7) promotes both thymopoiesis and mature T lymphocyte survival and proliferation. In experimental murine models of hematopoietic stem cell transplantation (HSCT), reconstitution of the naïve T cell population from donor-derived HSC is enhanced by IL-7 treatment. Since HSC products for transplantation may also contain IL-7-responsive mature T lymphocytes, IL-7 treatment in allogeneic BMT could lead to exacerbation of graft-versus-host disease (GVHD). Using IL-7 deficient murine models, we have previously shown that IL-7 mediates survival of mature T lymphocytes and is necessary for pathogenesis of GVHD. In the present study, we determined whether GVHD could be prevented by blockade of IL-7 signaling with an anti-murine IL-7 receptor alpha chain (IL-7Rα ) antibody. In order to induce GVHD, C57/BL6 (H2Kb) recipient mice were lethally irradiated (1300 cGy) and co-transplanted with 4x106 lymph node (LN) and 1x106 T cell depleted (TCD) BM cells from MHC-mismatched allogeneic Balb/C (H2Kd) donor mice. Following transplantation, the allogeneic BMT recipients were intraperitonally injected with either the anti-murine IL-7Rα antibody, SB14 (100μg/mouse/week) or PBS for 5 weeks. GVHD-related mortality and morbidity were decreased in allogeneic recipients treated with anti-IL-7Rα anti-body compared to the PBS treated groups. Anti-IL-7Rα antibody treatment significantly increased survival in the B6 mice (70%, n=20) for up to 5 months when compared to the PBS treated B6 recipients (20%, n=20 [p<0.005]). Histological examination of the anti-IL-7Rα anti-body treated B6 mice showed no evidence of GVHD in the skin, gut, or thymus. The overall GVHD clinical index of anti-IL-7Rα antibody treated allogeneic recipients was significantly lower than that of the PBS treated animal (p<0.05). The recovery of donor CD4+ or CD8+ T cells in the spleen and lymph nodes of the antibody treated recipients was significantly lower than the PBS treated animals by day 30 post-transplantation. Even though IL-7 signaling is essential for the development of T lymphocytes in the thymus, anti-IL-7Rα antibody treatment did not prevent donor-derived thymopoiesis. Histological analysis of thymic tissues revealed that anti-IL-7Rα antibody treated recipients have normal thymic cortical and medullary microenvironments whereas PBS recipients displayed a lack of cortical and medullary distinction and decreased thymic cellularity at day 30 and 250 following transplantation. Furthermore, anti-IL-7Rα antibody treated recipients were able to generate naïve T lymphocytes (CD62+ CD44−) whereas most donor T cells in the periphery of PBS treated recipients with GVHD had a memory phenotype (CD62− CD44+). Collectively, these findings suggest that the blockade of IL-7 signaling by anti-IL-7Rα antibody treatment not only inhibits occurrence of GVHD in the early phase of post-allogeneic BMT but also maintains host thymic capacity and improves T cell reconstitution.

Interleukin‐7 signalling is sufficient to phenotypically and functionally prime human CD4+ naïve T cells

Interleukin-7 (IL-7) is produced by bone marrow and lymphoid stromal cells and is involved in the synthesis, survival and homeostasis of T cells. These attributes are the basis for current strategies to utilize IL-7 as an immune modulator for several clinical conditions to replenish depleted T-cell numbers. Because we had previously determined that IL-7 can induce potent human immunodeficiency virus replication in the otherwise non-permissive CD4(+) naive T-cell compartment, we evaluated here the impact of IL-7 on the phenotype and functional potential of naive CD4(+) T cells in an attempt to understand the mechanism of this induction. We demonstrate that IL-7 mediated the up-regulation of CD25, CD95 and human leucocyte antigen-DR, while it did not alter the expression of CD45RO, CD69, CD40, or CD154. Examination of the cytokine profile of IL-7-treated naive T cells using a Type1/Type2 Proteome Array indicated a remarkable IL-7-mediated induction of interferon-gamma production, while the other cytokines evaluated (IL-2, IL-12, tumour necrosis factor-alpha, IL-4, IL-5, IL-10 and IL-13) were not affected. Intracellular staining of IL-7-treated naive T cells for interferon-gamma verified the Proteome data. IL-7 did not induce cell cycle proliferation of naive CD4(+) T cells, as evaluated by 7-AAD/pyronin immunostaining and carboxyfluorescein diacetate succinimidyl ester dye tracking. IL-7 treatment of naive CD4(+) T cells induced their ability to prime monocytes, as was indicated by induction of CD80 and CD86 expression on monocytes cocultured with IL-7-treated naive CD4(+) T cells. Collectively, these data indicate that IL-7 signalling is sufficient to phenotypically and functionally prime human CD4(+) naive T cells independent of antigen stimulation.

Interleukin-7 improves reconstitution of antiviral CD4 T cells

We evaluated whether long-term (2 months) administration of interleukin-7 (IL7) hastens immune recovery in baboons rendered severely lymphopenic by total body irradiation and antithymocyte globulin (ATG). Four baboons were treated with recombinant baboon IL7 and three baboons with placebo. Median CD4 T cell count at the end of IL7/placebo treatment was higher in the IL7-treated animals (2262 vs. 618/μl, P = 0.03). This appeared to be a result of peripheral expansion rather than de novo generation. Median cytomegalovirus (CMV)-specific IFNγ-producing CD4 T cell count at the end of IL7/placebo treatment was higher in the IL7-treated animals (122 vs. 1/μl, P = 0.03). All animals were pretransplant cytomegalovirus-seropositive. One animal died at the end of IL7 treatment; necropsy showed extensive T cell infiltration of kidneys and lungs. In conclusion, IL7 stimulates the expansion of CD4 T cells, including functional antiviral cells. Clinical risk–benefit ratio needs to be evaluated.

DF3/MUC1 Signaling In Multiple Myeloma Cells Is Regulated by Interleukin-7

The human DF3/MUC1 transmembrane protein is aberrantly expressed in multiple myeloma cells and other B cell malignancies. The regulation of MUC1 in B cells and its potential function as a signaling molecule are unknown. The present results demonstrate that interleukin-7 (IL-7) stimulates MUC1 expression in multiple myeloma cells. The results also demonstrate the IL-7 induces binding of MUC1 to the Lyn tyrosine kinase. The MUC1 C-terminal subunit binds directly to Lyn through interactions with the Lyn SH3 and SH2 domains. Activation of Lyn in response to IL-7 stimulation results in increased tyrosine phosphorylation of the MUC1 C-terminal subunit. In vitro and in vivo studies show that Lyn phosphorylates MUC1, at least in large part, on a YEKV site in the MUC1 cytoplasmic tail. The functional significance of the MUC1-Lyn interaction is supported by the demonstration that Lynmediated phosphorylation of MUC1 on YEKV induces binding of MUC1 and the βcatenin signaling protein. In concert with these results, IL-7 treatment is associated with binding of MUC1 to βcatenin and targeting of the MUC1 βcatenin complex to the nucleus. These findings indicate that IL-7 regulates MUC1 expression and function in multiple myeloma cells.Key Words MUC1, IL-7, multiple myeloma, Lyn, •-catenin.

Administration of interleukin-7 after allogeneic bone marrow transplantation improves immune reconstitution without aggravating graft-versus-host disease

Prolonged immunodeficiency after allogeneic bone marrow transplantation (BMT) causes significant morbidity and mortality from infection. This study examined in murine models the effects of interleukin-7 (IL-7) given to young and middle-aged (9-month-old) recipients of major histocompatibility complex (MHC)-matched or -mismatched allogeneic BMT. Although administration of IL-7 from day 0 to 14 after syngeneic BMT promoted lymphoid reconstitution, this regimen was ineffective after allogeneic BMT. However, IL-7 administration from day 14 (or 21) to 27 after allogeneic BMT accelerated restoration of the major lymphoid cell populations even in middle-aged recipients. This regimen significantly expanded donor-derived thymocytes and peripheral T cells, B-lineage cells in bone marrow and spleen, splenic natural killer (NK) cells, NK T cells, and monocytes and macrophages. Interestingly, although recipients treated with IL-7 had significant increases in CD4(+) and CD8(+) memory T-cell populations, increases in naive T cells were less profound. Most notable, however, were the observations that IL-7 treatment did not exacerbate graft-versus-host disease (GVHD) in recipients of an MHC-matched BMT, and would ameliorate GVHD in recipients of a MHC-mismatched BMT. Nonetheless, graft-versus-leukemia (GVL) activity (measured against 32Dp210 leukemia) remained intact. Although activated and memory CD4(+) and CD8(+) T cells normally express high levels of IL-7 receptor (IL-7R, CD127), activated and memory alloreactive donor-derived T cells from recipients of allogeneic BMT expressed little IL-7R. This might explain the failure of IL-7 administration to exacerbate GVHD. In conclusion, posttransplant IL-7 administration to recipients of an allogeneic BMT enhances lymphoid reconstitution without aggravating GVHD while preserving GVL.

Interleukin-7 Is Trophic for Embryonic Neurons and Is Expressed in Developing Brain

Interleukin-7 (IL7) is a hematopoietic cytokine with critical functions in both B- and T-lymphocyte development. In this study, we find that IL7 exhibits trophic properties in the developing brain as well. Treatment of cultures of embryonic brain with exogenous IL7 increases neuronal survival and results in greater numbers of cells manifesting neurite outgrowth. As demonstrated with single-cell cultures, IL7 acts directly to promote neuronal survival. Expression of the mRNA encoding the high-affinity IL7 receptor (IL7R) is observedin vitroin neurons as well as in subventricular zone progenitor cells. Phosphorylation of p59fyn, which is activated by IL7 in pre-B cells and is thought to be important in neural development, occurs rapidly following IL7 treatment of cultured embryonic neurons. Additionally, the expression of c-mycmRNA, which is modulated by IL7 in lymphoid cells, is upregulated by IL7 in the same CNS cultures. Finally, the messenger RNAs encoding IL7 and IL7R are expressedin vivoin developing brain. The direct neurotrophic properties of IL7 combined with the expression of ligand and receptor in developing brain suggest that IL7 may be a neuronal growth factor of physiological significance during central nervous system (CNS) ontogeny.

Regulatory effects of interleukin-7 on renal tumor infiltrating lymphocytes.

Biological therapy using a combination of lymphokine and tumor infiltrating lymphocytes (TILs) is a new approach to the treatment of patients with advanced cancer. To improve the potency of TILs, new cytokines with T-cell stimulatory effects used alone or in combination with interleukin-2 (IL-2) are currently being investigated. We have studied the effect of interleukin-7 (IL-7) on TILs derived from renal cell carcinoma. Our data demonstrated that five of ten TILs proliferated in response to IL-7 alone. This proliferative response was 73-90% less than that obtained with IL-2 alone. The use of IL-7 plus IL-2 resulted in a 1.2- to 4.7-fold increase in proliferation of six of ten TILs compared with IL-2 alone. IL-7-driven TIL growth was consistently blocked by anti-IL-2, anti-IL-2R and anti-IL-7 antibodies (37.2%, 41.6% and 82.2% suppression, respectively). The expression of IL-2 receptors was also significantly increased in the presence of IL-7 or IL-7 phytohemagglutinin (40.6 + 3.8 and 72.5 + 1.5). In comparison with IL-2, IL-7 treatment was associated with a decrease in CD56 (46.3% +/- 19 vs 10% +/- 4.9) and increase in CD3 (29.3% +/- 12 vs 73% +/- 6.4) and CD4 (19.3% +/- 15 vs 58% +/- 10). These studies suggest that in some renal TILs, IL-7 and IL-2 can have a synergistic proliferative effect. The IL-7 stimulatory effect appears to be mediated via both an IL-2 pathway and an IL-7-independent pathway.