Strategies for improving antitumor activity utilizing IL-2: preclinical models and analysis of antitumor activity of lymphocytes from patients receiving IL-2.
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Clinical Trials as Topic↗
Biomedical subjects
J A Hank
Publications and source records attributed to J A Hank.
Serum CD25 levels during interleukin-2 therapy: dose dependence and correlations with clinical toxicity and lymphocyte surface sCD25 expression.
Using an enzyme-linked immunosorbent assay (ELISA), we have measured serum levels of a soluble form of the p55 subunit of the interleukin-2 receptor complex, soluble CD25 (sCD25), at regular intervals in the sera of 51 pediatric and adult cancer patients receiving recombinant human interleukin-2 (IL-2). The IL-2 was administered in repetitive weekly cycles alone or in combination with lymphokine-activated killer (LAK) cells. Levels of CD25 correlated with clinical toxicities reflected by nadir blood pressures, percentages of weight gained, and minimum Karnofsky performances during IL-2 therapy. Coadministration of autologous in vitro activated LAK cells together with IL-2 did not significantly affect the pattern of sCD25 release relative to administration of IL-2 alone. Examination of sCD25 release in response to different doses of IL-2 revealed a statistically significant dose effect of IL-2 on the sCD25 levels in patient sera. In addition, the level of sCD25 in patient sera also correlated strongly with expression of CD25 on the surface of peripheral blood lymphocytes (PBL) obtained from patients following IL-2 therapy. These studies demonstrate the utility of the sCD25 ELISA as a clinical tool for monitoring patients on treatment regimens that include IL-2.
Antigens, CD↗
In vivo effects of multiple cycles of recombinant interleukin-2 (IL2) on peripheral granulocyte-macrophage hematopoietic progenitors circulating in the blood of cancer patients.
The numbers of peripheral blood (PB) granulocyte-macrophage colony forming units (CFU-GM) were evaluated in five patients treated with multiple weekly cycles of recombinant interleukin-2 (IL2). A 4.5-12 fold increase in the number of CFU-GM was evident within 8 days after the beginning of the treatment. The maximal increase in the absolute numbers of CFU-GM/ml blood caused by the IL2 treatment, ranged from 14 to 57 times the baseline values and was reached after two or three cycles of IL2. IL2-activated PBMC, added in vitro to the PBMC of a normal donor did not modify the number of CFU-GM present in the donor PBMC. CFU-GM were also recovered from frozen samples of in vivo IL2-activated PBMC.
Drug Administration Schedule↗
Analysis of T cell receptor beta and gamma genes from peripheral blood, regional lymph node and tumor-infiltrating lymphocyte clones from melanoma patients.
A total of 199 T cell clones from two melanoma patients were derived from progenitor T cells from recurrent melanoma, regional lymph nodes (either involved or uninvolved with malignancy) and peripheral blood by inoculating single cells directly into the wells of microtiter plates before in vitro expansion. The surface marker phenotype of most clones was CD4+CD8-, although some were CD4-CD8+. Genomic DNA prepared from all clones was analyzed by Southern blot hybridization using T cell receptor (TCR) beta and gamma gene probes, seeking clones with identical TCR gene rearrangement patterns as direct evidence for in vivo progenitor T cell clonal amplification. Probing HindIII-digested DNA with TCR beta and TCR gamma probes revealed several clones with identical TCR gene rearrangement patterns. These clones had subsequent probing of BamHI-digested DNA with TCR beta and TCR gamma probes, which showed all but 2 clones to have distinct rearrangement patterns. These analyses provide clear molecular evidence for in vivo polyclonal CD4+ T cell populations in each of several separate immune compartments in these patients.
Adult↗
BLT-esterase activity following in vitro and in vivo activation of human lymphocytes with interleukin-2. In vivo IL-2 induces BLT-esterase.
BLT-esterase and cytolytic activity by human in vitro and in vivo generated Lymphokine Activated Killer (LAK) cells were measured. Lysates made from peripheral blood lymphocytes (PBL) of both normal donors and cancer patients receiving IL-2 therapy were assayed for BLT-esterase activity in a spectro-photometric assay. Cytotoxicity of PBL was measured in a 51Cr-release assay. Both BLT-esterase activity and cytotoxicity increased when normal-donor PBL were stimulated in vitro with IL-2, with greater activities at higher IL-2 concentrations. The activities also increased over time, peaking at 6 days of in vitro stimulation. Patient PBL had increased BLT-esterase and cytotoxic activities after 4 weeks of in vivo IL-2 treatment. This association of BLT-esterase activity and cytotoxicity with IL-2 activation is consistent with the model that LAK cytotoxicity is mediated by secretion of BLT-esterase associated cytolytic granules. Lymphocytes obtained after in vivo IL-2 treatment and cultured for 3-4 hours in IL-2 show markedly augmented cytotoxic activity but no increase in their BLT-esterase activity. These results indicate that the increased cytotoxicity observed after this brief pulse of in vitro IL-2 following in vivo IL-2 treatment must result from effects of IL-2 other than the production of more esterase-containing cytolytic granules.
Cell Survival↗
Activation of human T cells obtained pre- and post-interleukin-2 (IL-2) therapy by anti-CD3 monoclonal antibody plus IL-2: implications for combined in vivo treatment.
The role of activated T cells in the mediation of antitumor responses has been documented in several experimental models. In some of these, interleukin-2 (IL-2) has been used as a means to induce and expand the antitumor effects of the T cells. IL-2 has been tested in clinical trials for cancer treatment. Surprisingly, T cells appear to be inactivated by IL-2 in these clinical trials. T cells obtained from peripheral blood after IL-2 therapy showed decreased responses to mitogens and alloantigens, did not proliferate in vitro in response to IL-2, and did not mediate non-major histocompatibility complex-restricted cytotoxicity or targeted lysis in the presence of bispecific monoclonal antibodies. In this study, we present evidence that these post-IL-2 therapy T cells are not irreversibly inactivated; they can be activated in vitro by anti-CD3 monoclonal antibody together with IL-2 to upregulate the p55 component of the IL-2 receptor and proliferate. Nevertheless, following activation by anti-CD3 and IL-2, the level of targeted T-cell cytotoxicity mediated by the post-IL-2 therapy T cells was significantly lower than that by pre-IL-2 therapy T cells. Although in vivo treatment with IL-2 alone induces natural killer (NK) cells to mediate lymphokine-activated killer activity, these data suggest that the T-cell lytic function is inhibited by this treatment and only partially reversible by subsequent T-cell receptor activation using anti-CD3 mAb. Exposure of T cells to anti-CD3 mAb prior to in vivo IL-2 treatment generates T-cell lytic activity in vitro. These results, together with preclinical murine studies, suggest that a combined in vivo protocol of anti-CD3 mAb and IL-2, starting first with the anti-CD3 mAb, may cause activation of the T cells in addition to the activation of NK cells and thus warrant clinical testing.
Antibodies, Monoclonal↗
Immunological effects of levamisole in vitro.
Levamisole, an anthelminthic drug with immunological properties, has recently been reported to have antitumor activity when administered with 5-fluorouracil in patients with Duke's C colorectal carcinoma. The mechanism of this antitumor effect is unknown, but has been postulated to be related to levamisole's immunomodulatory properties. To define further the immunomodulatory activities of levamisole, we studied the in vitro effects of levamisole on monocyte and lymphocyte cytotoxicity, activation, and proliferation; induction of cytokine-induced proteins; and expression of tumor-associated antigens. Experiments utilized peripheral blood mononuclear cells from normal donors incubated in the presence of increasing concentrations of levamisole (0.1 to 100 micrograms/ml). Levamisole had no consistent effect on induction of 2',5'-oligoadenylate synthetase activity or indoleamine-2,3-dioxygenase activity, or production of tumor necrosis factor. Levamisole had no effect on monocyte cytotoxicity or expression of HLA-DR, HLA-DQ, HLA-DP, and the Fc receptor. Similarly, levamisole had no significant effect on NK or LAK cytotoxicity or the immunological activation of T-lymphocytes, assessed by expression of CD3, CD4, CD8, CD16, CD25, and CD56. Proliferation of lymphocytes from normal donors, patients with benign polyps, and patients with malignancies, with or without IL-2 or irradiated LS174T cells, was not significantly increased overall. No significant enhancement in the expression of three tumor-associated antigens (880364, NRCO-4, and ING-1) and the intercellular adhesion molecule-1 (ICAM-1) antigen on four human cancer cell lines was observed following in vitro exposure to levamisole. We conclude that levamisole is not a potent modulator of the immune parameters we examined, and that the mechanism behind the unique clinical interaction between levamisole and 5-fluorouracil in colorectal carcinoma remains to be identified.
2',5'-Oligoadenylate Synthetase↗
Prolonged interleukin-2 (IL-2) treatment can augment immune activation without enhancing antitumor activity in renal cell carcinoma.
Preliminary studies involving small numbers of patients have suggested that interleukin-2 (IL-2) administered by continuous infusion in repetitive weekly cycles using doses of 3 x 10(6) U/M2/day is immunologically active and can induce tumor responses in patients with renal cell carcinoma. This study was designed to examine both the immunological and clinical effects of prolonged infusion IL-2 given by repetitive weekly cycles; first at moderate doses for 4 weeks as an impatient followed by lower doses of IL-2 for up to 5 months. Prolonged IL-2 treatment was investigated because previous studies revealed that patients had a return to their baseline immune status within 4 weeks after completing IL-2 treatment. Twenty-five patients (including 18 with renal cell carcinoma) were treated with one of two regimens utilizing IL-2 as sole therapy. These regimens were designed to induce augmented and prolonged immune activation based upon in vitro and in vivo data. Though patients on both arms of the study demonstrated sustained lymphocytosis, increase in numbers of natural killer cells, and induction of lymphokine-activated killer activity with prolonged IL-2 administration, only 1 out of the 18 patients with renal cell carcinoma demonstrated a sustained partial antitumor response to therapy. Furthermore, several patients demonstrated profound immune activation, without any evidence of tumor regression. The lack of clinical responses in these patients showing marked activation of LAK cytotoxicity suggests that other variables must also influence the likelihood of antitumor effects for patients receiving IL-2 therapy.
Adult↗
The influence of autologous lymphokine-activated killer cell infusions on the toxicity and antitumor effect of repetitive cycles of interleukin-2.
Twenty patients with refractory malignancies were treated with a protocol evaluating the addition of ex vivo-activated autologous lymphokine-activated killer (LAK) cells to a clinically tolerable interleukin-2 (IL-2) regimen (four weekly cycles of human recombinant IL-2 at 3 x 10(6) U/m2/day by continuous infusion for 4 days/week). Sixteen patients completed their induction month of therapy, two had a partial response, six had stable disease, and eight had progressive disease. Four patients had clinical toxicity preventing completion of the induction month of therapy, and one of these patients died during therapy. Significant clinical toxicities included decreased performance status, weight gain, catheter-related thromboses, infectious complications, fever, hypotension, and dyspnea or hypoxemia requiring oxygen. Thus, the addition of LAK cell infusions to this IL-2 regimen did not cause a noticeable change in antitumor response rate but did not cause more severe toxicity.
Adult↗
Increased expression of the interleukin 2 (IL-2) receptor beta chain (p70) on CD56+ natural killer cells after in vivo IL-2 therapy: p70 expression does not alone predict the level of intermediate affinity IL-2 binding.
The expression of the 70-kD beta subunit of the interleukin 2 receptor (IL-2R) has been examined on peripheral blood lymphocytes (PBL) obtained from patients receiving systemic infusions of IL-2. Using monoclonal antibodies directed against p70, flow cytometric analyses revealed a greater than threefold increase in expression of the IL-2R beta chain on CD56+ natural killer (NK) cells from post-IL-2 therapy PBL relative to pre-therapy cells. The level of p70 expression on the post-therapy cells was three- to fourfold greater (based on fluorescence intensity) than the level of p70 expression on YT cells, an NK-like cell line that expresses approximately 12,000 intermediate affinity IL-2 binding sites/cell. Despite the high level of p70 expression, in 125I-IL-2 binding assays only 790-1,290 intermediate affinity IL-2 binding sites/cell were detected on post-therapy cells from six patients. These data represent the first report of increased p70 expression after in vivo IL-2 administration and suggest a requirement for at least one additional subunit for the formation of functional intermediate affinity IL-2Rs. Furthermore, the presence on the surface of post-therapy NK cells of excess p70 that does not bind IL-2 with intermediate affinity implies that the formation of intermediate affinity IL-2Rs is not solely determined by the level of p70 expression, and that the response of NK cells to IL-2 might be regulated by altering the expression of p70 or some other IL-2R subunit.
Antibodies, Monoclonal↗
Augmentation of antibody dependent cell mediated cytotoxicity following in vivo therapy with recombinant interleukin 2.
Monoclonal antibodies (mAB) with tumor specificity are able to enhance the immunological specificity of interleukin 2 (IL-2)-activated lymphokine activated killer (LAK) cells. Antibodies may also be used to broaden the range of tumor types susceptible to immune mediated cytotoxicity by the activated LAK cells. In these studies, mAB with relative tumor specificity were used to target immunologically activated effector cells in an in vitro antibody dependent cell mediated cytotoxicity (ADCC) assay. The mAB included: 3F8 and 14.G2a, which are both specific for neuroblastoma and melanoma and recognize ganglioside GD2, and mAB ING-1, a mouse-human chimeric antibody with constant regions from human IgG1 and kappa chains and variable regions from a mouse mAB that binds to a broad range of human adenocarcinomas. Each of these mAB was able to mediate ADCC with fresh effector cells and antibody binding targets. When peripheral blood mononuclear cells were obtained from cancer patients prior to and following in vivo therapy with interleukin 2, a significant increase was noted in ADCC activity by peripheral blood mononuclear cells obtained following IL-2 therapy. Inclusion of IL-2 in the medium during the cytotoxic assay with mAB further boosted ADCC. The total activity seen was often greater than the sum of the independent LAK activity and standard ADCC activity. The cells responsible for this ADCC had the CD16+ Fc receptor. Combining IL-2 with mAB in clinical tumor therapy may lead to a wider range of tumor types being responsive to immunotherapy and may also enhance the efficacy of therapy by specifically targeting activated effector cells to tumor cells recognized by mAB. Our results provide strong support for the testing of these hypotheses in clinical trials by combining in vivo treatment with IL-2 and mAB able to mediate ADCC.
Antibodies, Monoclonal↗
Human T cell receptor-gamma delta-expressing T-cell lines recognize MHC-controlled elements on autologous EBV-LCL that are not HLA-A, -B, -C, -DR, -DQ, or -DP.
HLA-loss variants of an EBV-transformed B lymphoblastoid cell line (EBV-LCL) 721 were used to investigate whether human MHC molecules other than known class I or class II were involved in autologous T cell responses. Bulk lymphocyte cultures of purified T cells primed to an autologous variant EBV-LCL that fails to express HLA-class II and has reduced cell surface HLA-class I expression, and oligoclonal TCR-gamma delta-bearing lines derived from them, could lyse both this EBV-LCL and an independently derived, class II expressing autologous variant EBV-LCL that bears no HLA-A, -B, or -C, suggesting the presence of additional HLA-like restriction elements. Cold target inhibition of cytolysis mediated by these lines indicated that a shared or cross-reactive MHC controlled restriction element other than the known MHC determinants was retained by the EBV-LCL variants. Single-cell derived clones from these T cell lines which expressed only the TCR-gamma delta showed this same target cell specificity pattern, proving recognition of MHC-controlled determinants by autologous gamma delta T cells. Anti-gamma delta antibody could inhibit cytolysis by the gamma delta-expressing lines, suggesting that the TCR-gamma delta was involved in recognition of the EBV-LCL targets. Flow cytometric analysis with separate HLA-reactive antibodies indicated that the restriction element for these cytolytic responses is a molecule serologically cross-reactive with HLA-B and -C Ag, yet is a determinant that cannot be HLA-A, -B, -C, -DR, -DQ or -DP.
Antigens, CD↗
Specific recognition of human leukemic cells by allogeneic T cells: II. Evidence for HLA-D restricted determinants on leukemic cells that are crossreactive with determinants present on unrelated nonleukemic cells.
Transplantation of immunocompetent cells present within allogeneic bone marrow has been associated with the elimination of residual host leukemia, both in animal tumor models and in patients receiving marrow transplants for leukemia. This observation has been called the "graft-versus-leukemia effect." We have attempted to study this phenomenon in vitro by characterizing the cytolytic response of T cells from normal donors after in vitro activation with allogeneic leukemic cells. As expected, most T cells that react against an allogeneic patient's leukemic cells recognize their foreign HLA antigens and lyse the patient's nonleukemic remission lymphoid cells. In addition, we have shown that a small fraction of the T cells recognize and lyse foreign leukemic targets without lysis of nonmalignant remission targets from the same leukemic patient. These T cells have been isolated and characterized as CD3+, CD4+ cells expressing the alpha/beta T cell receptor (TCR). Their lysis appears to reflect specific antigen recognition mediated via the CD3-TCR complex and interactions involving the CD4 receptor. Some of these "leukemic specific" T cell lines, which are restricted by HLA class II molecules, can also lyse occasional nonleukemic cells from certain unrelated donors. This recognition appears to involve crossreactive determinants shared by the leukemic cells and the unrelated allogeneic nonleukemic cells. These specific interactions may represent an in vitro model of the graft-versus-leukemia effect.
Antigens↗
Natural killer cells activated by interleukin 2 treatment in vivo respond to interleukin 2 primarily through the p75 receptor and maintain the p55 (TAC) negative phenotype.
Interleukin 2 (IL-2) induced activation of unstimulated resting natural killer (NK) cells or resting T-cells initially occurs following binding of IL-2 through the p75 receptor that is expressed primarily by these cells. However, this IL-2/p75 interaction induces TAC chain synthesis and formation of high affinity IL-2 receptor required for the proliferation of resting peripheral blood lymphocytes. In this study, we present data indicating that NK cells activated by in vivo IL-2 treatment, in contrast to resting NK cells, respond and proliferate to further IL-2 in vitro using primarily the p75 receptor with only a minor component of cells responding through the high affinity receptor. These in vivo activated NK cells minimally expressed the TAC chain and maintained this TAC negative phenotype while proliferating in response to IL-2. The primary involvement of the p75 receptor in the proliferative response of these cells to IL-2 was demonstrated by the need for concentrations of IL-2 higher than 44 pM to obtain a significant response and by the dramatic inhibition of this response by anti-p75 monoclonal antibody. Anti-TAC monoclonal antibody inhibited only the poor proliferation obtained at low doses of IL-2 suggesting a minor role for TAC and high affinity IL-2 receptors. This was in contrast to the partial inhibition of proliferation by anti-p75 or anti-TAC observed in unstimulated pretherapy peripheral blood lymphocytes suggesting that these cells respond to IL-2 through both high affinity receptors and intermediate affinity p75 receptors. The T-cells isolated from in vivo activated peripheral blood lymphocytes, despite expressing TAC, were not responsive to IL-2, suggesting that these cells express predominantly nonfunctional low affinity TAC receptors. NK cells activated by IL-2 in vivo represent a unique model system of IL-2 dependent cells that respond and proliferate to IL-2 essentially through the p75 IL-2 receptor.
Antibodies, Monoclonal↗
Addition of interleukin-2 in vitro augments detection of lymphokine-activated killer activity generated in vivo.
The in vivo administration of repetitive weekly cycles of interleukin-2 (IL-2) to patients with cancer enhances the ability of freshly obtained peripheral blood lymphocytes (PBL) to lyse both the natural-killer(NK)-susceptible K562 and the NK-resistant Daudi targets. Lysis of both targets is significantly augmented by inclusion of IL-2 in the medium during the cytotoxicity assay. This boost is much greater for cells obtained following the in vivo IL-2 therapy than for cells obtained prior to the initiation of therapy or for cells from healthy control donors. In addition to direct lytic activity, the PBL obtained following in vivo IL-2 show a rapid increase in lymphokine-activated killer (LAK) activity with more prolonged in vitro IL-2 exposure, indicating that LAK effectors primed in vivo respond with "secondary-like" kinetics to subsequent IL-2 in vitro. Lymphocytes from healthy control individuals, cultured in IL-2 under conditions attempting to simulate the in vivo IL-2 exposure, function similarly to PBL obtained from patients following IL-2, in that low-level LAK activity was significantly boosted by inclusion of IL-2 during the cytotoxic assay and the cells also responded with secondary-like kinetics to subsequent IL-2 in vitro. The augmentation of the LAK effect was also dependent on the dose of IL-2 added during the 4-h 51Cr-release cytotoxicity assay, with higher doses of IL-2 having a more pronounced effect. While continuous infusion of IL-2 induces a greater cytotoxic potential per milliliter of blood obtained from patients, the peak serum IL-2 levels attained are greater with bolus IL-2 infusions. These pharmacokinetic results, together with the IL-2 dose dependence of LAK activity generated in vivo shown in this report, suggest that a combination of treatment with bolus IL-2 infusions superimposed on continuous IL-2 infusion may transiently expose IL-2 dependent LAK cells, activated in vivo, to higher concentrations of IL-2, facilitating their in vivo cytotoxic potential.
Cells, Cultured↗
Effects of interleukin-2 (IL-2) on human plasma lipid, lipoprotein, and C-reactive protein.
Six patients with confirmed malignant disease received four consecutive weekly cycles of human recombinant interleukin-2 (IL-2) 4 days/week, continuous iv. infusion, 3 X 10(6) U/m2/day. Plasma cholesterol decreased a mean of 7% within 24 hours after IL-2 infusion and decreased by 33% within 4 days. Plasma cholesterol was significantly lower than baseline concentration by day 21 (-21%), and day 25 (-41%) was significantly lower than day 21. Decreased plasma cholesterol was the result of decreased HDL and LDL cholesterol concentrations. Plasma triglyceride demonstrated a mean increase of 46% after 4 days of therapy and remained greater than baseline concentrations at all time points analyzed. Apolipoprotein AI and AII decreased concomitantly with HDL-cholesterol concentrations, whereas apolipoprotein B after an initial mean decrease of 17% during the first cycle was not significantly different from baseline during the fourth cycle. Apolipoprotein E and Lp(a) were not significantly affected by IL-2 treatment. Plasma C-reactive protein (CRP) increased by 79% within 24 hours of therapy, increased by 254% on day 4, then decreased to baseline concentrations by day 21 after 3 days off of IL-2. Day 25 CRP was elevated compared to both baseline and day 21 concentrations. IL-2 induced plasma lipoprotein changes may be due in part to the induction of interferon gamma.
Apolipoprotein A-I↗
The appearance of hypodense eosinophils during interleukin-2 treatment.
Based on membrane receptors, metabolic activity, and cell density, human eosinophils (EOSs) are a heterogeneous population of leukocytes. EOS heterogeneity translates into biologic significance, since low density cells can be metabolically more active and thus more capable of causing tissue injury. Efforts to identify mechanisms that lead to the development of hypodense EOSs have found that an in vitro exposure to cytokines reduces cell density and is associated with increased cell activity. Consequently, we evaluated the effect of an in vivo administration of interleukin-2 (IL-2) on the cell counts and density of circulating EOSs in six patients who received IL-2 as cancer biologic-modifier therapy. To determine the pattern of EOS density in relationship to IL-2 treatment, granulocyte suspensions were isolated from peripheral blood and then centrifuged over multiple discontinuous density Percoll gradients. During IL-2 treatment, the percentage of circulating hypodense EOSs increased significantly (p less than 0.01) until nearly all (97.6 +/- 1.6%) EOSs were hypodense (density less than 1.095 gm/ml). Similarly, the absolute blood EOS counts significantly increased throughout treatment. On completion of IL-2 therapy, the EOS counts and density distribution returned to pretreatment values. In contrast, no increase in blood EOS counts was observed in similar patients receiving interferon (gamma or beta) therapy. Our observations support a hypothesis that IL-2, either directly or, more likely, through the generation of other factors, participates in a change in EOS density that may, in turn, establish a subpopulation of cells with altered metabolic activity.
Adult↗
Depressed in vitro T cell responses concomitant with augmented interleukin-2 responses by lymphocytes from cancer patients following in vivo treatment with interleukin-2.
Peripheral blood lymphocytes obtained from cancer patients receiving interleukin-2 (IL-2) on two separate clinical protocols were evaluated for their in vitro responses to IL-2, alloantigens, and PHA. IL-2 in vivo induced enhanced in vitro proliferative responses to IL-2 and diminished in vitro proliferative responses to phytohemagglutinin (PHA) and alloantigens. Alloinduced cytotoxic T cell responses were also depressed following in vivo IL-2. We examined the kinetics of the in vitro proliferative response to PHA and IL-2 and found that while the response of lymphocytes primed in vivo with IL-2 to PHA was depressed at all times during the 2 week in vitro exposure, the response to IL-2 peaked earlier and higher than did the response to IL-2 by lymphocytes obtained prior to IL-2 therapy. These contrasting effects on antigen-induced T cell responses vs. IL-2 induced nonspecific proliferative and cytotoxic responses suggest the importance of dose and timing of IL-2 administration when used to enhance antigen-specific T cell responses or as an immune enhancing agent combined with vaccines.
Cell Division↗