Long-term IL-2 Research Articles

Rapamycin improves the long-term T-cell memory and protective efficacy of tuberculosis subunit vaccine

The formation of long-lived T-cell memory is a critical goal of vaccines against intracellular pathogens like Mycobacterium tuberculosis (M. tuberculosis). In this study, to access the adjuvant effect of rapamycin on tuberculosis subunit vaccine, we treated mice with rapamycin during the course of vaccination and then monitored the vaccine-specific long-term memory T cell recall responses and protective ability against mycobacterial organisms. Compared with the mice that received vaccine alone, rapamycin treatment enhanced the vaccine induced long-term IFN-γ and IL-2 recall responses, promoted the development of TCM (central memory) like cells and improved the long-term proliferative ability of lymphocytes. Long-duration (total 53 days) of low-dose rapamycin (75 μg/kg/day) treatment generated stronger vaccine-specific memory T cell responses than short-duration treatment (total 25 days). Moreover, rapamycin improved the vaccine's long-term protective efficacy, which resulted in a better reduction of 0.89-log10 CFU of mycobacterial organisms in the lungs compared with control without rapamycin treatment. These findings suggest that rapamycin may be considered in designing TB subunit vaccine regimens or as potential adjuvant to enhance vaccine-induced T cell memory response and to prolong the longevity of vaccine's protective efficacy.

Challenges in αCD38-chimeric antigen receptor (CAR)-expressing natural killer (NK) cell-based immunotherapy in multiple myeloma: Harnessing the CD38dim phenotype of cytokine-stimulated NK cells as a strategy to prevent fratricide

Background aimsAdoptive cell therapy with chimeric antigen receptor (CAR)-expressing natural killer (NK) cells is an emerging approach that holds promise in multiple myeloma (MM). However, the generation of CAR-NK cells targeting CD38 is met with obstacles due to the expression of CD38 on NK cells. Knock-out of CD38 is currently explored as a strategy, although the consequences of the lack of CD38 expression with regards to engraftment and activity in the bone marrow microenvironment are not fully elucidated. Here, we present an alternative approach by harnessing the CD38dim phenotype occurring during long-term cytokine stimulation of primary NK cells. MethodsPrimary NK cells were expanded from peripheral blood mononuclear cells by long-term IL-2 stimulation. During expansion, the CD38 expression was monitored in order to identify a time point when introduction of a novel affinity-optimized αCD38-CAR confered optimal viability, i.e. prevented fratricide. CD38dim NK cells were trasduced with retroviral vectors encoding for the CAR trasngene and their functionality was assessed in in vitro activation and cytotoxicity assays. ResultsWe verified the functionality of the αCD38-CAR-NK cells against CD38+ cell lines and primary MM cells. Importantly, we demonstrated that αCD38-CAR-NK cells derived from patients with MM have increased activity against autologous MM samples ex vivo. ConclusionsOverall, our results highlight that incorporation of a functional αCD38-CAR construct into a suitable NK-cell expansion and activation protocol results in a potent and feasible immunotherapeutic strategy for the treatment of patients with MM.

Pyrazinamide enhances persistence of T-cell memory induced by tuberculosis subunit vaccine LT70

Repurposing anti-tuberculosis drugs with adjuvant properties in vaccination has double benefits for the control of tuberculosis. In this study, to verify the immunomodulatory effect of the tuberculosis drug pyrazinamide (PZA) on tuberculosis subunit vaccine-induced memory T cell response, we treated mice with PZA during the course of vaccination and then monitored the vaccine-specific T cell memory responses. Compared with the mice that received LT70 alone, we found that the mice co-administrated with PZA and LT70 did not produce a higher frequency of multifunctional CD4+ T lymphocytes at 8-week post-vaccination, but the T lymphocytes produced stronger long-term IL-2 response rather than IFN-γ recall response and had higher long-term proliferating potential upon antigen stimulation at 28-week post-vaccination. In addition, the memory T cells from PZA-treated mice showed superior IFN-γ recall response after twice antigen stimulations in vivo and in vitro respectively. Together, the findings show that PZA treatment during the course of vaccination contributes to inducing TCM-like cells and enhances vaccine-induced T-cell long-term immunological memory, which would be helpful for designing novel vaccination and therapeutic strategies for tuberculosis.

Comprehensive analysis of the immunomodulatory effects of rapamycin on human T cells in graft-versus-host disease prophylaxis

Graft-versus-host disease (GVHD) is a major cause of toxicity after allogeneic hematopoietic cell transplantation (allo-HCT). While rapamycin (RAPA) is commonly used in GVHD prophylaxis in combination with a calcineurin inhibitor (CNI), the understanding of its mechanism of action on human T cells is still incomplete. Here, we performed an extensive analysis of RAPA effects on human T cells in a humanized mouse model of GVHD, in ex-vivo T cell cultures and in patients given RAPA plus tacrolimus as GVHD prophylaxis after nonmyeloablative allo-HCT. We demonstrate that RAPA mitigates GVHD by decreasing T cell engraftment and differentiation, inhibiting CD8+ T cell activation and increasing the long-term IL-2 secretion, thereby supporting regulatory T cell (Treg) proliferation. In contrast, graft-versus-leukemia effects were not abrogated, as RAPA-treated T cells had increased resistance to apoptosis and retained their effector function and proliferative capacity upon re-stimulation. Importantly, we found that RAPA impact on Treg and CD8+ T cells was closely dependent upon IL-2 signaling and that therapeutic options interfering with IL-2, such as calcineurin inhibitors, antagonize the IL-2-dependent promotion of Treg mediated by RAPA. Our results suggest that RAPA immunological efficacy could be improved in combination with drugs having possible synergistic effects such as the hypomethylating agent 5-azacytidine.

Long-Term IL-2 Incubation-Induced L-type Calcium Channels Activation in Rat Ventricle Cardiomyocytes.

The following study examined the impact of IL-2 on Ca2+ channel activity in the event of several hours' incubation in IL-2. The right ventricle free wall for action potential measurements was isolated and perfused with Tyrode solution. The whole-cell voltage clamp experiments were performed on enzymatically isolated single cardiomyocytes. The whole-cell voltage clamp recording of Ca2+ currents was performed using the Cs+-based pipette and bath solutions. The protocol with depolarizing prepulse (- 40mV) was used to inactivate both Na+ current and Ca2+T-type current. The L-type Ca2+ current was elicited by a series of 250ms depolarizing square pulses with 10mV increments. At the 15th minute of continuous recording, the peak density at 0mV was - 3.036 ± 0.3015 pA/pF under IL-2 and - 3.008 ± 0.3452 pA/pF in control conditions. The IL-2 in moderate concentration (1ng/mL) has no acute effects on ICa.L in rat ventricular cells. In contrast, to the lack of acute effects, the long-term incubation with IL-2 (2h or more) produced a prominent enhancement of Ca2+L-type current. In rat, ventricular myocardium IL-2 (1ng/mL) produced a very gradual prolongation of subendocardial APs which reached a maximal extent after 3-4h of treatment. The patch clamp study shows an IL-2-induced ICa.L current activation, while the action potential studies on multicellular ventricular preparations suggest an IL-2-induced L-type Ca2+ channel participation in the development of AP.

The Neutrophil-to-Lymphocyte Ratio as A Prognostic Factor For Long-Term Interleukin-2 Use in Renal Cell Carcinoma

The neutrophil-to-lymphocyte ratio (NLR), a measure of systemic inflammation, has been reported to be a predictive parameter of patient prognosis. We speculated that the NLR is decreased in renal cell carcinoma (RCC) patients in whom interleukin (IL)-2 is effective. In this study, we retrospectively examined the usefulness of the NLR as a prognostic factor using three cases of RCC treated with long-term IL-2. In all three cases, the NLR remained less than 2.7 during IL-2 treatment, suggesting its effectiveness as a marker. During interferon-α or molecular targeted drug therapy, the NLR was unstable, regardless of treatment effectiveness, but a sudden rise in the NLR tended to suggest massive radiographic progression and worse prognosis. The results suggested that the NLR might serve as a useful marker for therapies when determining prognosis.

Long-term IFN-γ and IL-2 response for detection of latent tuberculosis infection in healthcare workers with discordant immunologic results

Discordant results between the interferon-gamma release assays (IGRAs) and tuberculin skin test (TST) are common in latent tuberculosis infection (LTBI). We evaluated whether the measurement of IFN-γ and interleukin (IL)-2T-cell responses, after prolonged Mycobacterium tuberculosis-specific antigen stimulation, can be used as adjunctive biomarker for LTBI detection in subjects with discordant results between TST and QuantiFERON-Gold In-Tube (QFT). 196 healthcare workers were screened for LTBI and in 90 of those participants, the QFT was repeated after 18h, and IFN-γ/IL-2 immune response was measured after 72h long-term stimulation. Of the 196 patients, 34 had positive, 155 negative, and 7 indeterminate QFT results. Discordant TST+/QFT− results were found in 29 (14.7%) patients, of whom 6 (20.6%) were Bacillus Calmette–Guerin (BCG) vaccinated. None of 23 non-BCG vaccinated subjects showed a specific IFN-γ immune response after 18h nor 72h of incubation, whereas 3/23 (13.04%) discordant subjects produced a specific long-term IL-2 response, which might reflect a LTBI status. In LTBI group (TST+/QFT+) both cytokine levels were increased after long-term in comparison to short-term stimulation. No significant long-term IFN-γ/IL-2 secretion was detected in control group (TST−/QFT−). Taken together, our data showed that the 87% of discordant patients who did not respond to the long-term assay, as controls subjects, were judged LTBI negative.The use of classic QFT and long-term IL-2 response may have a potential role to clarify the LTBI status in individuals in whom the diagnosis of LTBI is uncertain due to the discordance of the available diagnostic tests, such as TST and IGRA.

AB0169 IL-2 Therapy Decreases Total Number of Kidney Infiltrating CD4+ T Cells and Reduces the Cellular Activity of CD4+ Effector T Cells in NZB/W Mice

BackgroundSystemic lupus erythematosus (SLE) is an autoimmune disease characterized by an acquired IL-2 deficiency, which leads to a homeostatic imbalance between regulatory T cells (Treg) and effector T cells (Tcon)...

AB0193 IL-2 therapy in murine lupus nephritis leads to an expansion of intrarenal FOXP3+ regulatory T cells

BackgroundSystemic lupus erythematosus (SLE) is an autoimmune disease characterized by an acquired IL-2 deficiency, which leads to a homeostatic imbalance between regulatory T cells (Treg) and effector T cells. Recently,...

Improvement of NK cells functional activation after long-term IL-2 stimulation in vitro from ovarian neoplasia patients

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Pesticide induced marrow toxicity and effects on marrow cell population and on hematopoietic stroma

Long term inhalation of toxic pesticides used for the domestic and industrial purposes have been shown to cause moderate to severe hematotoxicity and increased incidence of several marrow degenerative diseases, specifically hypoplastic bone marrow failure condition in humans. The progression of pesticide induced hematotoxicity and the exact underlying mechanisms of toxicity that play major role in limiting normal hematopoiesis are not quite well explained. In this present study, we have developed an animal model of hypoplastic bone marrow failure following pesticide exposure to show the deleterious effects of toxic pesticides on mouse hematopoietic system. Here we have presented the results of studying long-term marrow explant culture, IL-2, IL-3 and IL-5 receptors expression profile, fibroblast colony forming unit (CFU-F), hematopoietic progenitor cell colony formation and caspase-3 expression by the bone marrow cells. We have also identified the expression levels of several extracellular apoptosis markers (CD95/Fas) and intracellular apoptosis inducer proteins (pASK1, pJNK, caspase-3 and cleaved caspase-3) in the bone marrow cells of pesticide exposed mice. The long-term marrow explant culture demonstrated the impairment in proliferation of the stromal cells/stromal fibroblasts in culture. Decreased IL-2, IL-3 and IL-5 receptors expression profile essentially hinted at the suppressed cytokine activity in the pesticide exposed marrow. CFU-F analysis showed the defect in functional maturation of the stromal fibroblasts. The decreased hematopoietic progenitor cell colony formation indicated the toxicity induced inhibition of cellular proliferation and functional maturation of hematopoietic stem/progenitor cells in pesticide exposed marrow. We have detected a sharp increase in the expression levels of both the extracellular Fas-antigen and intracellular apoptosis inducer proteins in the bone marrow cells of pesticide exposed mice that explained well, the apoptosis pathway involved following marrow toxicity. The decreased proliferation and functional maturation of marrow stromal cells and hematopoietic progenitors with subsequent increase in marrow cellular apoptosis following pesticide toxicity provided the base necessary for explaining the increased incidence of hypoplastic bone marrow failure in humans exposed to moderate to high concentrations of pesticides.

T cells expanded in presence of IL-15 exhibit increased antioxidant capacity and innate effector molecules

Persistence of effector cytotoxic T lymphocytes (CTLs) during an immunological response is critical for successfully controlling a viral infection or tumor growth. Various cytokines are known to play an important part in regulating the immune response. The IL-2 family of cytokines that includes IL-2 and IL-15 are known to function as growth and survival factors for antigen-experienced T cells. IL-2 and IL-15 possess similar properties, including the ability to induce T cell proliferation. Whereas long-term IL-2 exposure has been shown to promote apoptosis and limit CD8+ memory T cell survival and proliferation, it is widely believed that IL-15 can inhibit apoptosis and helps maintain a memory CD8+ T-cell population. However, mechanisms for superior outcomes for IL-15 as compared to IL-2 are still under investigation. Our data shows that human T cells cultured in the presence of IL-15 exhibit increased expression of anti-oxidant molecules glutathione reductase (GSR), thioredoxin reductase 1 (TXNDR1), peroxiredoxin (PRDX) and superoxide dismutase (SOD). An increased expression of cell-surface thiols, intracellular glutathione, and thioredoxins was also noted in IL-15 cultured T cells. Additionally, IL-15 cultured T cells showed an increase in cytolytic effector molecules. Apart from increased level of Granzyme A and Granzyme B, IL-15 cultured T cells exhibited increased accumulation of reactive oxygen (ROS) and reactive nitrogen species (RNS) as compared to IL-2 cultured T cells. Overall, this study suggests that T cells cultured in IL-15 show increased persistence not only due to levels of anti-apoptotic proteins, but also due to increased anti-oxidant levels, which is complimented by increased cytolytic effector functions.

KHYG-1 and NK-92 represent different subtypes of LFA-1-mediated NK cell adhesiveness

Novel cancer cellular therapy approaches involving long-term ex vivo IL-2 stimulated highly cytotoxic natural killer (NK) cells are emerging. However, adhesion properties of such NK cells are not very well understood. Herein, we describe the novel observation of permanently activated alphaLbeta2 integrin leukocyte function-associated antigen (LFA)-1 adhesion receptor in long-term IL-2 activated NK cells and the permanent NK cell lines KHYG-1 and NK-92. We show that such cytokine activated NK effectors constitutively adhered to the LFA-1-ligand ICAM-1, whereas binding to the lower affinity ligand ICAM-3 required additional exogenous activating conditions. The results demonstrate an extended conformation and an intermediate affinity state for the LFA-1 population expressed by the NK cells. Interestingly, adhesion to ICAM-1 or K562 induced pronounced cell spreading in KHYG-1, but not in NK-92, and partially in long-term IL-2 stimulated primary NK cells. It is conceivable that such differential adhesion characteristics may impact motility potential of such NK effectors with relevance to clinical tumor targeting. KHYG-1 could be a useful model in planning future targeted therapeutic approaches involving NK effectors with augmented functions.

In vivo expansion of naive and activated CD4 + CD25 + FOXP3 + regulatory T cell populations in interleukin-2–treated HIV patients

HIV-1 infection is characterized by a progressive decline in CD4(+) T cells leading to a state of profound immunodeficiency. IL-2 therapy has been shown to improve CD4(+) counts beyond that observed with antiretroviral therapy. Recent phase III trials revealed that despite a sustained increase in CD4(+) counts, IL-2-treated patients did not experience a better clinical outcome [Abrams D, et al. (2009) N Engl J Med 361(16):1548-1559]. To explain these disappointing results, we have studied phenotypic, functional, and molecular characteristics of CD4(+) T cell populations in IL-2-treated patients. We found that the principal effect of long-term IL-2 therapy was the expansion of two distinct CD4(+)CD25(+) T cell populations (CD4(+)CD25(lo)CD127(lo)FOXP3(+) and CD4(+)CD25(hi)CD127(lo)FOXP3(hi)) that shared phenotypic markers of Treg but could be distinguished by the levels of CD25 and FOXP3 expression. IL-2-expanded CD4(+)CD25(+) T cells suppressed proliferation of effector cells in vitro and had gene expression profiles similar to those of natural regulatory CD4(+)CD25(hi)FOXP3(+) T cells (Treg) from healthy donors, an immunosuppressive T cell subset critically important for the maintenance of self-tolerance. We propose that the sustained increase of the peripheral Treg pool in IL-2-treated HIV patients may account for the unexpected clinical observation that patients with the greatest expansion of CD4(+) T cells had a higher relative risk of clinical progression to AIDS.

Vasoactive intestinal peptide 10-28 enhances natural killer cell cytotoxicity (134.84)

Abstract Objective: Vasoactive intestinal peptide (VIP) and its synthetic analog VIP14-28 enhance NK cytotoxicity. This prompted us to study interaction of the naturally occurring peptide and orphan ligand VIP 10-28 with NK. Results: VIP10-28 stimulation (10-8-10-10 M, 30 min.) increased NK-92 cytotoxicity against K562 max. from 52% +/-2.6% SEM (control) to 68% +/-2.6% SEM (E:T 1:1), similar to long-term IL-2 stimulated NK from different donors (4/6), max. from 38% +/-4.2 SEM (control) to 51% +/-0.9% SEM (E:T 1:1). VIP10-28 did not seem to induce degranulation, since granzyme B levels remained unchanged in NK-92. However, stimulation with 10-8-10-10 M VIP10-28 for 5- 60 min. significantly induced tyrosine phosphorylation with ERK identified as one of the stimulated kinases. We used Informational Spectrum Method (ISM) to predict VIP10-28 NK receptor interactions. ISM results suggested potential binding of VIP10-28 to LFA-1α (F = 0.03, peptide residues 16-24) and with lower affinity to CD44 or MAC-1, but unlikely to NKG2D, -C, -A, NKp30, -44, -46, CD56, CD94, KIR2DL4, NKR-P1, CD45 or VIP receptors VPAC-1/ VPAC-2. Conclusion: The neuroendocrine peptide VIP10-28 induces increased NK cytotoxicity potentially through LFA-1 signaling pathways involving tyrosine kinase activation of ERK kinases.

Does complete response (CR) with systemic therapy (SRx) translate into long term survival in stage IV melanoma (MM)?

9043 Background: The impact of SRx on survival of patients (pts) with MM remains uncertain. We wanted to describe the pts with stage IV MM who had CRs, their Rx and its impact on survival. Methods: The 567 chemo-naive pts with stage IV non-choroidal MM, excluding surgical CRs, were selected from 647 pts treated in 9 trials. Results: The median age was 48 years and 366 were males. ECOG P.S., was 0/1/2/3 in 274/213/58/22 and their stage was M1a/M1b/M1c in 76/99/392 pts respectively. Their # of involved visceral sites was 0/1/2/≥3 in 96/217/156/98 respectively. 196pts had Liver metastasis. The %CRs by Rx were 3.23/8.43/13.08 for CVD/C-paclitaxel-D (CRx, #217)/CVD-IFN ± tamoxifen (CIRx, #83)/CVD-IFN+IL-2 (BCRx, #267) respectively. The median survival by response (CR/no-CR) was 78/10.5 mos. for BCRx and 46.4/8.1 for non-BCRx respectively. The survival of BCRx pts was superior at 5 years (7.78% vs. 2%, p = 0.0018) and 10 years (5.99% vs. 0.33%, p = 0.00001) compared to non-BCRx pts. The overall, BCRx and non-BCRx (CRx + CIRx) results were as follows (see table). Conclusions: CR does translate into long-term survival and IL-2 based Rx gives CRs more often than other therapies. %CR: BCRx Non-BCRx “P” value All pts 13.08 4.67 P < 0.0001 Males 17.14 4.71 P < 0.0001 ECOG P.S. = 0 17.88 4.88 P = 0.001 Skin/Mucosal 12.16 4.33 P < 0.002 Stage M1a/M1b 23.66 7.32 P = 0.0033 <2 Met. Visc. Sites 17.61 4.55 P = 0.0002 NL LDH 17.36 5.75 P < 0.001 No liver met 15.73 5.18 P < 0.001 No significant financial relationships to disclose.

A phase II study of intrapleural immuno-chemotherapy, pleurectomy/decortication, radiotherapy, systemic chemotherapy and long-term sub-cutaneous IL-2 in stage II–III malignant pleural mesothelioma☆

From therapeutic nihilism to extremely aggressive management, there is a wide range of possibilities in the treatment of malignant pleural mesothelioma (MPM). Unfortunately, there is little evidence as regards the best treatment to offer to the MPM patients. In 1999, we started a phase II study based on the multimodality treatment of stage II-III MPM, the results of which have been analysed and reported. From 1999 to 2004, 49 patients with IMIG stage II-III MPM underwent a multimodality treatment including: intrapleural pre-operative interleukin 2 (IL-2, 18x10(6) UI/day per 3 days), pleurectomy/decortication, intrapleural post-operative epidoxorubicin (25mg/m2 per 3 days), IL-2 (18x10(6) UI/day per 3 days), adjuvant radiotherapy (30Gy), systemic chemotherapy (cisplatin 80 mg/m2 day 1, gemcitabine 1250 mg/m2 day 1 and 8 up to 6 courses) and long-term sub-cutaneous IL-2 (3x10(6) UI/day 3 days per week). There were 41 males and 8 females with a median age of 61 years (range 41-77). All the patients had a diagnosis of MPM by thoracoscopy before inclusion. We did not experience any post-operative mortality. The histology was: 39 epitheliomorf, 6 bifasic and 4 sarcomatous. According to the IMIG the post-operative staging was III in 40 cases and II in 9 cases. With a median follow-up of 59 months (range 14-81) 13 patients are still alive and the median actuarial survival is 26 months (31 and 21 months for stage II and III, respectively). Only the Performance Status at the diagnosis affected survival significantly. The multimodality treatment we adopted for stage II-III MPM was feasible, well tolerated by most of the patients and produced a favourable outcome. New targeted therapies are awaited for further improvements in the treatment of this disease.

Editorial commentA phase II study of intrapleural immunochemotherapy, pleurectomy/decortication, radiotherapy, systemic chemotherapy, and long-term subcutaneous IL-2 in stage II–III malignant pleural mesothelioma

Objective: From therapeutic nihilism to extremely aggressive management, there is a wide range of possibilities in the treatment of malignant pleural mesothelioma (MPM). Unfortunately, there is little evidence as regards the best treatment to offer to the MPM patients. In 1999, we starteda phaseIIstudybasedonthemultimodalitytreatmentofstageII—IIIMPM,theresultsofwhichhavebeenanalysedandreported.Methods: From 1999 to 2004, 49 patients with IMIG stage II—III MPM underwent a multimodality treatment including: intrapleural pre-operative interleukin 2 (IL-2, 18 10 6 UI/day per 3 days), pleurectomy/decortication, intrapleural post-operative epidoxorubicin (25 mg/m 2 per 3 days), IL-2 (18 10 6 UI/day per 3 days), adjuvant radiotherapy (30 Gy), systemic chemotherapy (cisplatin 80 mg/m 2 day 1, gemcitabine 1250 mg/m 2 day 1 and 8 up to 6 courses) and long-term sub-cutaneous IL-2 (3 10 6 UI/day 3 days per week). Results: There were 41 males and 8 females with a medianage of 61 years(range 41—77). All the patients had a diagnosis of MPM bythoracoscopy before inclusion. We didnot experience any postoperative mortality. The histology was: 39 epitheliomorf, 6 bifasic and 4 sarcomatous. According to the IMIG the post-operative staging was III in 40 cases and II in 9 cases. With a median follow-up of 59 months (range 14—81) 13 patients are still alive and the median actuarial survival is 26 months (31 and 21 months for stage II and III, respectively). Only the Performance Status at the diagnosis affected survival significantly. Conclusions: The multimodality treatment we adopted for stage II—III MPM was feasible, well tolerated by most of the patients and produced a favourable outcome. New targeted therapies are awaited for further improvements in the treatment of this disease. # 2007 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.

Interruption of antiretroviral therapy blunts but does not abrogate CD4 T-cell responses to interleukin-2 administration in HIV infected patients

Intermittent administration of interleukin (IL)-2 to HIV infected patients leads to CD4 T-cell expansions that are associated with decreased CD4 T-cell turnover. IL-2 is under evaluation in antiretroviral therapy (ART) interruption studies, but it is unclear how the emergence of viremia may affect CD4 expansions. CD4 T-cell responses were evaluated in 27 HIV infected patients on long-term intermittent IL-2 therapy who underwent ART interruption immediately after an IL-2 cycle ('IL-2/off') and compared with responses from a previous IL-2 cycle while on continuous ART ('IL-2/on'). Immunophenotypic analysis, including intracellular Ki67 staining, of cryopreserved peripheral blood mononuclear cells was performed. CD4 T-cell increases, in naive and central memory CD4 T-cell subsets, were observed in the IL-2/on (106 and 327 cells/microl, respectively) and IL-2/off (84 and 184 cells/microl, respectively) cycles 1 month following IL-2 administration. These increases were greater during the IL-2/on cycle (P = 0.05, P = 0.01, respectively). In both cycles, the change in CD4 T-cell count correlated with the change in CD4/CD25 T cells. In the IL-2/off cycle, the change in the proportion of CD4 T cells expressing Ki67 was associated with both the changes in viral load (r = 0.64, P = 0.001) and the changes in CD4 T cells (r = -0.56, P = 0.01). IL-2 administration followed by ART interruption led to significant, although blunted, CD4 T-cell increases. IL-2 induced CD4 T-cell increases in the setting of emergent viremia were associated with decreased CD4 T-cell activation that counteracted the viremia-induced increases in CD4 T-cell activation.

Long-term low-dose IL-2 enhances immune function in common variable immunodeficiency.

Common variable immunodeficiency (CVID) is a primary immunodeficiency disease characterized by hypogammaglobulinemia and lack of antibody production. Numerous T cell defects have been described, including reduced gene expression and production of IL-2. Since some of the T cell defects could be explained by lack of IL-2, we have been investigating the effects of in vivo IL-2 treatment. Here, a long-acting form of IL-2, PEG-IL-2, was given for 12-18 months to 15 randomly chosen CVID subjects, in comparison to 39 CVID subjects who served as controls. After 6 to 12 months of treatment, T cell proliferative responses to mitogens and to IL-2 were significantly enhanced; proliferative responses to tetanus and candida antigens increased up to 50-fold. Four of eight subjects immunized with the neoantigen bacteriophage &phi;X 174 displayed increased antibody responses after treatment. Treated subjects recorded reduced, but not overall statistically significant, days of bronchitis, diarrhea, and joint pain. These data indicate that IL-2 might serve as an adjuvant to therapy in some subjects with CVID, enhancing T cell functions and reversing T cell anergy in most.