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Regulatory Potential of Fever-Range Whole Body Hyperthermia on Langerhans Cells and Lymphocytes in an Antigen-Dependent Cellular Immune Response¹

Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263

	Abstract

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The febrile response is one of the most common features of infection and inflammation. However, temperature is rarely a variable in experimental immunological investigations. To determine whether the thermal microenvironment has any immunoregulatory potential in an Ag-dependent response, we applied a mild fever-range whole body hyperthermia (FR-WBH) protocol to BALB/c mice experiencing the contact hypersensitivity (CHS) reaction. We observed that the timing of this FR-WBH treatment relative to the different phases of the CHS response was crucial to the outcome. FR-WBH treatment before sensitization with a 0.5% FITC solution resulted in a depressed CHS response. This appears to be due to direct effects of FR-WBH on epidermal Langerhans cell trafficking to the draining lymph nodes. In contrast, application of FR-WBH directly after application of the elicitation dose of FITC solution resulted in an enhanced reaction. This result correlates with increased homing of lymphocytes to the site of elicitation. Overall, these data have important implications regarding the role of thermal changes experienced during infection and the clinical use of FR-WBH relative to immunotherapeutic strategies.

	Introduction

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The fever response is one of the most commonly recognized features of illness, and yet the purpose of the increase in core body temperature that is associated with fever remains the most poorly understood aspect of the acute inflammatory response (1). Indeed, while much is known about the various events which lead to fever (2), very little is known about what specific benefits the thermal component of fever may have in the effector arm of the immune response. This is surprising in face of the knowledge that the febrile response to infection is strongly conserved evolutionarily, as even ectotherms exhibit behavioral fevers that dramatically improve survival following infections (3, 4). More specifically, febrile temperatures have been found to enhance the early inflammatory response in lizards, leading to increased granulocyte emigration at the local site of the infection (5). Studies have also revealed that movement to warmer environments can facilitate the successful eradication of infection in mammals (6). In addition, fever responses are known to occur at significant metabolic cost in higher vertebrates (7). Even in humans, a recent report has revealed that the use of aspirin as an antipyretic prolonged illness in subjects infected with influenza A (8). Collectively, these facts support the notion that there is a beneficial role for fever-range (FR)³foot;2936f3;10;ZPICKFOOT;> hyperthermia since it is unlikely that the need for this large energy expenditure would have been retained if it has no survival value.

In addition to the possible benefits of FR hyperthermia on infectious diseases, a mild temperature, long duration (i.e., FR) whole body hyperthermia (WBH) protocol has been found to significantly improve antitumor effects of chemotherapeutics (9) and, by itself, delay tumor growth and metastases (10, 11) without the toxicity to normal tissues that higher temperature protocols engender (12, 13). Preclinical studies such as these have led to the clinical use of FR-WBH, where the safety of this protocol has been assured (Ref. 14 and W. G. Kraybill, T. Olenki, S. S. Evans, J. R. Ostberg, K. A. O’Leary, J. Gibbs, and E. A. Repasky, manuscript in preparation), and trials maximizing the efficacy of this treatment in combination with other therapies in malignant disease are presently underway.

As alluded to above, one possible mechanism by which FR-WBH exerts its antitumor effects is by stimulating immune responses. Indeed, the origins of hyperthermia as a cancer treatment modality are correlatively linked with some of the earliest immunotherapy literature, since it has been recognized that the bacterial toxins given to cancer patients to stimulate their immune systems also resulted in strong fever responses (15). To maximize any potential clinical benefits, it is now critical to completely understand the molecular and immunological mechanisms by which febrile temperatures affect immune responses and antitumor activity. Thus, we decided to characterize the effects of FR-WBH on a classical Ag-dependent cellular immune reaction, the contact hypersensitivity (CHS) response.

	Materials and Methods

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Mice

BALB/c female mice (8- to 10-wk old; Taconic Laboratories, Germantown, PA) were used in all experiments with age-matched controls. All protocols involving these mice were approved by the Roswell Park Institute Animal Care and Use Committee.

CHS reaction

Mice were sensitized with 400 µl of 0.5% FITC in a 1:1 solution of acetone:dibutyl phthalate on the shaved abdomen. Mock-sensitized animals were treated with 400 µl of the acetone:dibutyl phthalate solution alone. Six days later, baseline ear thickness was measured with Quick Mini thickness-gauge calipers (Mitutoyo, Kawasaki, Kanagawa, Japan) and ear swelling responses were elicited with application of 10 µl of the same FITC solution to both the dorsal and ventral surfaces of the ear. Changes in ear thickness compared with baseline were recorded at 6.5, 12, 24, 36, 48, and 72 h after elicitation of the response.

FR-WBH

To prevent dehydration, mice were injected with 1 ml of nonpyrogenic saline i.p. immediately before being placed in microisolator cages preheated to 38.8°C. The cages (5 mice per cage) were then placed in an environmental chamber with preheated fresh air (Memmert model BE500; Memmert, East Troy, WI). Within 20 min, the average core body temperatures of the mice were raised from 37.5°C (normal core temperature of mice) to 39.5–40°C, and this body temperature was maintained for 6 h by adjusting the temperature of the environmental chamber. Core temperatures were monitored with the Electronic Laboratory Animal Monitoring System from Biomedic Data Systems (Maywood, NJ) using nonexperimental BALB/c mice that had 14 x 2.2-mm microchip transponders s.c. implanted into the dorsal thoracic area. Variations in temperature readings between animals are reproducibly within 0.2°C of the mean. Control mice were kept at room temperature and subjected to the same manipulations as that of the heated mice. All experiments were started at approximately the same time each day (7:30–9:30 a.m.) to avoid the possible influence of diurnal cycling.

Flow cytometric analysis

Cells (5–10 x 10⁵) were washed with PBS and 200-µl suspensions were then incubated on ice with either of the following mAbs: 0.1 µg of R35-95 (rat IgG2a isotype control), 0.1 µg of RA3-6B2 (rat IgG2a anti-CD45R/B220), 0.1 µg of 53-2.1 (rat IgG2a anti-CD90.2/Thy 1.2), or 0.2 µg of 2.4G2 (anti-CD16/CD32 (FcIII/IIR); BD PharMingen, San Diego, CA). Those samples incubated with the rat mAbs were then washed before blocking with 5% normal goat serum (Life Technologies, Grand Island, NY) followed by incubation with 0.2 µg of PE-conjugated polyclonal goat anti-rat Ig (BD PharMingen). Those samples blocked with the anti-FcIII/IIR mAb were incubated with 0.02 µg of either PE-conjugated RB6-8C5 (anti-CD11c/integrin _x chain) or PE-conjugated HL3 (anti-CD11b/integrin _M chain). All samples were washed before fixing in 1x PBS containing 2% paraformaldehyde. Samples were then run within 36 h on a FACScan (BD Immunocytometry Systems, San Jose, CA), and two parameter histograms of FITC vs PE were analyzed using Winlist 2.01 software (Verity Software House, Topsham, ME).

Proliferation assays

Using round-bottom 96-well tissue culture plates, 2 x 10⁵ inguinal lymph node (LN) cells were incubated at 37°C in 5% CO₂ in a 200-µl final volume of RPMI 1640 medium, 10% FCS/well with or without 50 µg/ml FITC, or with 10 µg/ml PHA as positive control. On the third day of culture, 1 µCi of [³H]thymidine in 20 µl of RPMI 1640 medium, 10% FCS was added per well, and plates were harvested 6–8 h later using the Harvester 96 Mach III M (Tomtec, Hamden, CT). The glass fiber filtermats (Wallac, Turku, Finland) were allowed to dry, sealed with 5 ml of scintillation fluid in a MicroBeta sample bag (Wallac), and then counted using the 1450 MicroBeta Trilux Liquid Scintillation and Luminescence Counter (Wallac). The change in cpm (delta cpm) was calculated as the difference between those cell cultures that were incubated with medium alone and those that were incubated with FITC.

Statistical analysis

Unpaired Student’s t tests were used to compare the values of room temperature controls to that of WBH-treated mice at each time point. Values of p < 0.05 were considered to represent statistically significant differences.

	Results

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Timing of FR-WBH has differential effects on CHS

The CHS reaction involves the exposure of epidermal cells to haptens, where later challenge with the same hapten results in a delayed-type hypersensitivity response that can be measured. For these studies, core body temperatures of mice were raised to 39.5–40°C for 6 h either directly before or after the application of either the sensitizing or eliciting dose of FITC solution, and ear swelling responses were compared with those of room temperature control mice. No significant effect of FR-WBH was observed on the ear swelling response when the hyperthermia treatment occurred either directly after application of the sensitizing dose of FITC or before the application of the eliciting dose of FITC (Fig. 1, B and C). Treatment with FR-WBH directly before the mice were sensitized to the FITC solution resulted in a decreased ear swelling response (Fig. 1A). This result is comparable to that obtained with a microwave-induced, nonphysiological, high temperature (41.5°C) hyperthermia protocol applied directly before sensitization with oxazolone as hapten in CHS studies performed by Roszkowski et al. (16, 17). In contrast, FR-WBH treatment directly after application of the eliciting dose of FITC resulted in enhanced kinetics of the ear swelling response (Fig. 1D). This enhancement in ear swelling during the earlier time points of the response occurred in an Ag-dependent manner, as FR-WBH treatment of the mock-sensitized mice at any time did not induce any ear swelling responses.

View larger version (38K): [in this window] [in a new window]   FIGURE 1. Timing of FR-WBH relative to different phases of the CHS reaction has differential effects on the ear swelling response. Experimental BALB/c female mice were sensitized with a 0.5% FITC solution in acetone:dibutyl phthalate and mock-sensitized animals (mockS) were treated with the acetone:dibutyl phthalate solution alone. All mice received an elicitation dose of 0.5% FITC solution on their ears 6 days later, and changes in ear thickness compared with baseline were recorded at 6.5, 12, 24, 36, 48, and 72 h. A 6-h FR-WBH treatment was performed either directly before sensitization (A), after sensitization (B), before elicitation (C), or after elicitation (D) of the CHS reaction. n = 4–6 mice/group; *, p < 0.05 when using an unpaired Student’s t test to compare room temperature (RT) control and WBH-treated groups at each time point.

The Langerhans cells, which are the dendritic cells (DCs) of the skin, are the critical APCs in the CHS response, initiating sensitization to haptens by presenting Ags to T cells (18). Thus, to dissect the mechanism by which FR-WBH treatment decreased the CHS response as shown in Fig. 1A, the ability of the FITC⁺ Langerhans cells to migrate to the draining LNs of the abdomen, where they would then encounter a large pool of T cells, was analyzed. Interestingly, when WBH treatment was performed directly before application of the sensitization dose, fewer numbers of FITC⁺ cells were observed in confocal microscopic analysis of compressed inguinal LNs compared with RT controls at 1 and 2 days after sensitization (data not shown). Using flow cytometric analysis, 80% or more of the total number of FITC⁺ cells were also positive for the marker CD11b, which represents both myeloid-derived DC (e.g., Langerhans cells) and monocytes/macrophages—both of which can act as APCs (19). A smaller percentage of the FITC⁺ cells are positive for the DC-specific marker CD11c (19). The remaining percentage of FITC⁺ cells appear to be Thy1⁺ and we suspect are representative of Thy1⁺ epidermal T cells that have also left the skin for the draining LN. It is the numbers of FITC⁺CD11b⁺ and FITC⁺CD11c⁺ cells, but not the FITC⁺Thy1⁺ cells, that were decreased by FR-WBH pretreatment (Fig. 2A and data not shown). Furthermore, the FITC-specific proliferative responses of the inguinal LN cells were also decreased when mice were pretreated with FR-WBH (Fig. 3). FR-WBH pretreatment did not affect the polyclonal stimulation of inguinal LN cells with PHA (data not shown). Thus, it appears that the general trafficking of DCs from the epithelium to the draining LNs was altered by FR-WBH pretreatment in a manner that prevented normal sensitization to the FITC hapten. Interestingly, when FR-WBH was applied directly after sensitization, there were increased numbers of FITC⁺CD11b⁺ cells in the draining LN compared with controls (Fig. 2B). However, as with the ear swelling response (Fig. 1B), no effects were seen on the FITC-specific proliferative responses of inguinal LN cells when FR-WBH was applied after application of the sensitizing dose of Ag (data not shown).

View larger version (29K): [in this window] [in a new window]   FIGURE 2. FR-WBH treatment before or after sensitization alters the numbers of FITC+ APCs in draining LNs. Inguinal LN cell suspensions collected 1 day after sensitization from WBH-treated or room temperature (RT) control mice were analyzed by flow cytometry, to determine the numbers of FITC+ cells. Numbers of FITC+CD11b+ cells, which represent myeloid-derived DCs (or Langerhans cells) as well as monocytic APCs were determined per inguinal LN in mice that were treated with WBH directly before (A) or after (B) application of the sensitizing Ag dose. n = 3–4 mice/group; *, p < 0.05 when using an unpaired Student’s t test to compare room temperature control and WBH-treated groups.

View larger version (21K): [in this window] [in a new window]   FIGURE 3. FR-WBH treatment directly before sensitization results in decreased Ag-specific T proliferation in draining LNs. Inguinal LN cell suspensions were collected 5 days after sensitization from WBH-pretreated or room temperature control (c) mice and assayed for FITC-specific T proliferative responses by [3H]thymidine incorporation. n = 4 mice/group; *, p < 0.05 when using an unpaired Student’s t test to compare control and WBH-treated groups.

In contrast to the inhibitory effects of FR-WBH pretreatment before sensitization (Fig. 1A), we were also interested in determining potential mechanisms by which FR-WBH treatment directly after FITC challenge was able to enhance the CHS response as shown in Fig. 1D. When H&E cross-sections of the ears were analyzed, significantly enlarged blood vessels were transiently observed directly after a 6-h WBH treatment (Fig. 4, B and D). This is not surprising, for vasodilation is a common physiological response to overheating. However, heat-induced vasodilation could not be solely responsible for the increased ear swelling responses, as FR-WBH treatment was not sufficient to induce ear swelling in mock-sensitized mice (Figs. 1D and 4D).

View larger version (91K): [in this window] [in a new window]   FIGURE 4. FR-WBH treatment directly after elicitation enhances vascular volume in the ear. H&E cross-sections of the ear 6.5 h after application of FITC challenge from FITC-sensitized (A and B) and mock-sensitized (C and D) mice that were either left at room temperature (A and C) or treated with FR-WBH for 6 h (B and D). Arrowheads, blood vessels. Images (x4) are representative of three mice from each group.

To determine the effects of FR-WBH treatment on lymphocyte localization to the ear, microscopic analysis of H&E cross-sections of the ear were analyzed for numbers of lymphocytes in the blood vessels of the ear. Within the blood vessels, it was easy to identify lymphocytes based on morphology. FR-WBH treatment directly after application of the eliciting Ag resulted in significantly increased numbers of lymphocytes per ear in the blood vessels of the ear (Fig. 5). In contrast, significantly decreased numbers of total cells (Fig. 6A), specifically Thy1⁺ T lymphocytes (Fig. 6B), were observed in the ear draining LNs of WBH-treated mice. These observations suggest that application of FR-WBH during the elicitation response enhances the homing of Ag-specific T cells to the inflammatory site.

View larger version (29K): [in this window] [in a new window]   FIGURE 5. FR-WBH treatment directly after elicitation enhances lymphocyte numbers in the ear vasculature. Numbers of lymphocytes in ear vasculature were enumerated in single medial cross-sections per ear at x40 magnification. n = 5 mice/group; *, p < 0.05 when using an unpaired Student’s t test to compare room temperature control (c) and WBH-treated groups.

View larger version (20K): [in this window] [in a new window]   FIGURE 6. FR-WBH treatment directly after elicitation results in decreased numbers of lymphocytes in the ear-draining LN. Total numbers of cells (A) and numbers of Thy1+ lymphocytes (B) per ear draining LN were determined by trypan blue exclusion and flow cytometric analysis of LN cell suspensions, respectively. n = 4 mice/group; *, p < 0.05 when using an unpaired Student’s t test to compare room temperature (RT) control and WBH-treated groups.

	Discussion

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When considering the apparent stimulatory effect of FR-WBH alone on Langerhans cells both in vivo and in vitro (20), as well as its ability to enhance the numbers of FITC⁺ APCs in the draining LN (Fig. 2B), it is surprising that WBH treatment directly after sensitization does not enhance the CHS response (Fig. 1B). We first hypothesized that, within the 5- or 6-day lag between sensitization and elicitation, the kinetics of DC stimulation of LN T cells might have reached a plateau so that room temperature controls were able to "catch up" to any enhancement that occurred with FR-WBH treatment after sensitization. However, Ag-specific proliferative responses of inguinal LN cells collected only 3 days after sensitization did not appear to be increased by FR-WBH treatment directly after sensitization (data not shown). Thus, we now hypothesize that these results most likely reflect the inability of FR-WBH to enhance the already strong sensitizing capacity of the hapten acetone: dibutyl phthalate stimulus.

Although the ability of FR-WBH to affect DCs may be responsible for its inhibitory effects when applied directly before sensitization, it appears that the ability of this same treatment modality to affect lymphocytes plays a large role in its stimulatory effects when applied directly after challenge. Upon challenge with the eliciting dose of FITC, the hapten-specific part of the CHS response corresponds to the activation of hapten-specific primed T cells and occurs within 6 h (18). These T cells release chemokines which cause the skin to be infiltrated by neutrophils, resulting in a maximal ear swelling response that peaks 24 h after challenge (18). The ability of FR-WBH treatment to enhance the ear swelling response between 6 and 12 h after challenge suggests that it is the hapten-specific phase of the response that is most directly affected by the hyperthermia treatment. The data described here suggesting the ability of FR-WBH to influence Ag-specific T lymphocyte homing (Fig. 2) are also supported by previous reports that describe the ability of FR hyperthermia to enhance L-selectin and integrin-mediated adhesion of lymphocytes to vascular endothelium (21, 22). Thus, it appears that the ability of FR-WBH to alter lymphocyte trafficking results in the capacity of this treatment to increase early responsiveness to Ag challenge.

Based on the results of this study, we are interested in further evaluating the ability of FR hyperthermia to regulate both lymphocyte and epidermal Langerhans cell maturation- or activation-dependent migration. As inflammatory cytokines may play a role in this cell migration, it is important to note that this FR-WBH treatment alone does not induce systemic levels of IL-1, IL-6, or TNF- in mouse sera (23). However, WBH may induce changes in the local levels of cytokine production (e.g., in the skin microenvironment where Ag is applied). Future studies are presently underway to address these issues.

Regardless of the mechanism of action, it is clear that FR hyperthermia has a largely underappreciated capacity to regulate Ag-dependent immune responses. Studies such as ours illustrate the feasibility of harnessing the thermal element of fever to drive the desired immune response, whether it is inhibitory, in the case of autoimmunity or inflammatory disease, or stimulatory, in the case of malignant or infectious disease.

	Footnotes

 
¹ This work was supported in part by National Institutes of Health Grant CA71599, the Roswell Park Cancer Institute Core Grant CA16056-21, and a Training Fellowship from the Cancer Research Institute (to J.R.O.).

² Address correspondence and reprint requests to Dr. Julie R. Ostberg, Department of Immunology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263. E-mail address: Julie.Ostberg{at}RoswellPark.org

³ Abbreviations used in this paper: FR, fever range; WBH, whole body hyperthermia; CHS, contact hypersensitivity; LN, lymph node; DC, dendritic cell.

Received for publication March 13, 2001. Accepted for publication July 8, 2001.

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