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. 1999 Oct;98(2):267–272. doi: 10.1046/j.1365-2567.1999.00854.x

The preventive effects of incomplete Freund’s adjuvant and other vehicles on the development of adjuvant-induced arthritis in Lewis rats

L Zhang *, M Y Mia *, C L Zheng *, M A Hossain *, F Yamasaki †, O Tokunaga †, O Kohashi *
PMCID: PMC2326913  PMID: 10540226

Abstract

The present study showed a novel finding that the development of adjuvant-induced arthritis (AA) in Lewis rats was completely prevented by incomplete Freund’s adjuvant (IFA) injected 21 or 28 days before complete Freund’s adjuvant (CFA) challenge. Hexadecane also completely prevented AA and squalane, methyl oleate and pristane moderately prevented AA, though pristane by itself induced mild arthritis in two out of five rats. Concanavalin A-stimulated lymph node cells (LNCs) isolated from AA rats were able to adoptively transfer the severe polyarthritis to all the naive recipients or even to the IFA pretreated recipients with earlier onset and more rapid progression than those of AA. The LNCs from the donors who had been pretreated with IFA and subsequently challenged with CFA could induce mild arthritis in only two out of eight naive recipients, whereas all the recipients who were challenged with CFA immediately after intravenous injection of these LNCs developed significantly less severe arthritis. However, the LNCs from IFA-pretreated donors failed to prevent AA. According to the T helper type 1 (Th1)/Th2 paradigm, it was suggested that the adjuvant-active vehicles such as IFA, hexadecane, squalane, methyl oleate and pristane, can affect and deviate the Th1/Th2 balance of immune responses in host. CFA could promote the propagation of Th2 cells rather than Th1 cells in these vehicle-pretreated rats through as yet undetermined mechanisms, eventually resulting in the prevention of AA. Finally, we discussed a regulatory role of adjuvant vehicles for induction and suppression of AA.

INTRODUCTION

Adjuvant-induced arthritis (AA) in Lewis rats is a model of T-cell-mediated autoimmune disease resembling human rheumatoid arthritis (RA). AA can be induced by a single intradermal (i.d.) injection of complete Freund’s adjuvant (CFA) consisting of Mycobacterium tuberculosis (Mt) and incomplete Freund’s adjuvant (IFA) but AA cannot be induced by injection of IFA alone in the Lewis rats,1 suggesting the importance of Mt as an antigen and IFA as a coadjuvant.2 However, an i.d. injection of IFA alone was able to induce polyarthritis in DA rats, known as oil-induced arthritis (OIA).3 Similarly, it was also reported that pristane, a well-defined synthetic mineral oil, could induce severe and chronic arthritis in various rats or in mice, known as pristane-induced arthritis (PIA)4,5 and lipoidal amine (avridine), a strong interferon inducer, could induce polyarthritis in Lewis rats, known as avridine-induced arthritis (AIA).6 The clinical course and histology of OIA, PIA and AIA are indistinguishable from those of AA.3,4,6 The fact that OIA and AIA as well as AA can be passively transferred in the naive rats by the lymph node cells (LNCs) or spleen cells derived from arthritic rats suggests the involvement of immunological mechanisms for induction of these forms of arthritis.7–9 However, it is as yet uncertain what the specific antigen responsible for induction of these forms of arthritis might be, because IFA, pristane and other vehicles by themselves are intrinsically inert as immunogens.

The present studies described how a single i.d. injection of IFA or hexadecane, methyl oleate and squalane could not induce arthritis in Lewis rats, but rather prevented AA by subsequent injection of CFA. Furthermore, the LNCs derived from arthritic rats could adoptively transfer the severe arthritis either to the naive recipients, or even to the IFA-pretreated recipients. Finally, we discussed a regulatory role of adjuvant vehicles for induction and suppression of AA, and these vehicles exerted their effects possibly through imbalance of T helper type 1(Th1)/Th2 cells10 and/or cytokine networks.11

MATERIALS AND METHODS

Animals

Inbred Lewis rats were obtained from Charles River Japan, Inc. (Shiga, Japan). They were housed at the Center for Laboratory Animals of Saga Medical School, fed a sterile commercial diet and water ad libitum, and maintained by continuous brother and sister mating under specific pathogen-free conditions. At the age of 3–4 weeks females and males were separated and only females (7–10 weeks) were used in the experiments described here.

Preparation of CFA and induction of AA

Mycobacterium tuberculosis H37 Ra (Mt) and IFA were purchased from Difco Laboratories (Detroit, MI). The CFA was prepared as follows: 10 mg of H37 Ra was ground with a mortar and pestle and IFA was added drop by drop to a final volume of 1 ml. This preparation was kept in an incubator at 42° for 72 hr to improve the solubility of Mt in IFA. An equal volume of phosphate-buffered saline (PBS) was added drop by drop with continuous mixing in this preparation to make a good water-in-oil emulsion. For induction of AA, the rats were intradermally injected at the base of the tail with 0·1 ml of CFA.

Pretreatment of IFA or various vehicles

Squalane, pristane, methyl oleate and n-hexadecane were purchased from Wako Pure Chemical Industries, Ltd, Kobe, Japan). IFA and these vehicles were injected without forming an emulsion. The rats were intradermally injected in the left footpad with 50 μl of these various vehicles on the indicated days (1, 7, 14, 21, or 28 days) before CFA administration (day 0).

Clinical evaluation of AA

The severity of polyarthritis was assessed by standard methodology.12 Each paw was graded from 0 to 4 based on erythema, swelling and deformity of the joint. except the preinjected left paw. The highest achievable clinical scores would be 12. The rats were observed and scored every other day in a blinded fashion.

Adoptive transfer of AA with the concanavalin A-stimulated LNCs from various donors

The adoptive transfer experiments were carried out according to the method of Taurog et al.8,9 We used three different groups of donors in our experiments. In one group, donors received 0·1 ml of CFA injected i.d. into the tail base. In the second group, donors received the CFA injection 4 weeks after IFA intradermal injection (50 μl/rat, in the left footpad), all the members of these two groups were killed under ether anaesthesia 10–12 days after CFA administration and the inguinal lymph nodes (ILNs) were harvested. In the third group, donors received only IFA injection i.d. (50 μl/rat, in the left footpad) and were killed on day 28 after IFA injection to collect the ILNs. ILNs were mechanically homogenized to make single-cell suspension in Hanks’ balanced salt solution (HBSS, Sigma Chemicals Co., Poole, Dorset, UK) and washed three times in HBSS. These LNCs were incubated for 48 hr in 175-cm2 flasks (Falcan, Lincoln Paek NJ) with 3 μg/ml of concanavalin A (Con A; Sigma Chemical Co.) at a concentration of 3×106 cells/ml in 50 ml of RPMI-1640 medium (Flow Laboratories, Paisley, UK). The medium was supplemented with 100 mg/ml streptomycin, 100 U/ml penicillin G, 5×10−5 m 2-mercaptoethanol, 1% non-essential amino acid, and 10% heat-inactivated fetal calf serum (FCS) (Intergen Purchase, Kobe, Japan). Flasks were incubated at 37° in a humidified, 5% CO2 atmosphere. After 48 hr incubation, LNCs were harvested from cultured flasks by centrifugation and were washed twice with PBS, then 1·5×108 viable cells were resuspended in 1 ml PBS before intravenous injection into the tail vein of each syngeneic female recipient rat. After the transfer of LNCs, each recipient rat was examined daily and assigned a daily numerical clinical score based on the method described above.12 Except for the preinjected left paw, the highest achievable clinical scores would be 12.

Histology

The rats were killed under ether anaesthesia. Spleen, ILNs, paws and liver were fixed in 10% buffered formalin phosphate, for at least 2 days before decalcification. After decalcification, the sections were cut with a cryotome and then stained with haematoxylin and eosin. The stained sections were examined under a microscope for histopathological changes in the organs as previously described.13

Statistical analysis

Statistical analyses were conducted by using a commercially available microcomputer program (statview 4·5). Significant differences in arthritic score between two groups were determined at each point by the two-tailed Student’s t-test, and a P value of less then 0·05 was taken as significance.

RESULTS

Preventive effect of IFA on AA

All the rats developed the severe AA after i.d. immunization of CFA, whereas none of the rats (0/15) developed the disease when CFA was immunized i.d. 28 days after IFA administration (Fig. 1), indicating that IFA pretreatment completely prevented the development of AA. When IFA was intradermally injected 1, 7, 14, 21, or 28 days before CFA challenge, respectively (Table 1), all the rats which were pretreated with IFA 1 day before CFA challenge developed significantly less severe arthritis with delayed onset than that of the no pretreatment rats. The rats which were pretreated with IFA 7 days or 14 days before CFA challenge developed much less severe arthritis with lower incidence. None of the rats which were pretreated with IFA 21 or 28 days before CFA challenge developed the disease.

Figure 1.

Figure 1

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Preventive effect of IFA on adjuvant arthritis. All the rats were injected with CFA at the base of tail. It was either injected intradermally at the base of the tail without any pretreatment or 50 μl IFA was intradermally injected into the left footpad 28 days before CFA challenge. Each group consisted of 15 rats.

Table 1.

Preventive effect of IFA on the development of AA

graphic file with name imm0098-0267-t1.jpg
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Preventive effects of various vehicles on the development of AA

It is known that hexadecane, pristane, methyl oleate and squalane can be exchanged for IFA as a coadjuvant for the induction of AA or experimental allergic encephalomyelitis (EAE).2 We were interested to know whether or not these vehicles can also prevent the development of AA as IFA did. As shown in Table 2, hexadecane could completely prevent the development of AA. Methyl oleate prevented AA with lower incidence and significantly milder severity than that in the control group. Squalane could significantly reduce the severity of the disease in all of the rats. Pristane by itself induced very mild arthritis in two out of five rats (known as PIA4), whereas the other three rats did not develop the disease even after CFA challenge.

Table 2.

Preventive effects of various vehicles on AA

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Effects of LNCs from differently treated donors on induction or prevention of arthritis

As shown in Table 3, all the rats injected with 1·5×108 of Con A-stimulated LNCs derived from AA donors (group 1) developed the severe arthritis. The disease appeared 4–7 days after cell transfer and rapidly became severe within a few days. The same LNCs also induced severe arthritis in all the recipients who were pretreated with IFA 28 days before cell transfer (group 2). On the other hand, only two out of eight recipients (group 3) developed significantly milder arthritis after intravenous injection of the LNCs from the donors which had been pretreated with IFA and subsequently challenged with CFA. However, when the recipients (group 4) were immunized with CFA immediately after the intravenous injection of the same LNCs as in group 3, all the recipients developed much less severe disease than that of group 3 (P<0·05). Finally, the LNCs from the IFA-pretreated alone, without CFA challenge, donors never prevented the development of AA in the CFA-challenged recipients (group 5).

Table 3.

Effects of LNCs from differently treated donors on induction or prevention of arthritis

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Histological studies

In Fig. 2(b) and (d), all the rats were injected intravenously with the LNCs from AA rats. Figure 2(b) (adoptively transferred arthritis) showed the basically indistinguishable pathological changes of typical AA (Fig. 2a). There were various degrees of synovitis, tendinitis, periostitis and para-articular tissue granulation with eosinophilic fibrinous mass in the joint spaces, the predominant polymorpholeucocyte infiltration, intense connective tissue proliferation with pannus formation and subsynovial vascular dilatations and new bone formation. In contrast to these pathological changes, Fig. 2(c) (IFA-pretreated and CFA-challenged rats) showed no obvious inflammation or pathological changes. Figure 2(d) (rats IFA-pretreated followed by passive transferral of LNCs) showed similar changes to Fig. 2(a) and (b).

Figure 2.

Figure 2

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Histological studies of the inflamed joints. (a) an ankle joint of the arthritic rats 21 days after immunization with CFA. There is subsynovial connective tissue proliferation with acute inflammatory cell infiltration, Pannus formation, bone destruction and new bone formation; (b) inflamed joints of the recipient rats intravenously injected with LNCs from AA rats. Pathological changes are almost similar to (a); (c) no pathological changes were observed on the IFA-pretreated and then CFA-challenged rats and (d) severe arthritis of the recipients who were injected with the LNCs 28 days following IFA injection. Pathological changes are similar to (a) and (b). (H & E; magnifications: (a) ×332; (b) and (d) ×132; and (c) ×664).

DISCUSSION

The present study showed a novel finding that pretreatment with IFA or hexadecane completely prevented the development of AA in Lewis rats and other vehicles, such as squalane, methyl oleate and pristane, also moderately prevented AA. As a coadjuvant, it has been shown that IFA could be exchanged by many other vehicles, such as hexadecane, methyl oleate, squalane and pristane, for induction of AA given with mycobacterial antigens and for induction of EAE given with myelin basic proteins.2,14 Surprisingly, an i.d. injection of IFA could induce severe polyarthritis in the highly susceptible DA rats without mycobacterial antigens but not in Lewis rats.3,15 This oil-induced arthritis (OIA) is clinically and histologically indistinguishable from AA. By using DA, Lewis, F1 and F2 intercross rats, it was suggested that the susceptible genes of rat for OIA are located both within and outside the major histocompatibility complex (MHC; Oia 1).16 Furthermore, without any additional exogenous antigens, pristane could induce polyarthritis in rats and mice.4,5 The PIA was partly confirmed in the present study (Table 2). Avridine (lipoidal amine), a strong interferon inducer, could also induce polyarthritis in rats that was known as AIA.6 OIA, AIA and AA could be passively transferred to either irradiated rats or naive rats by LNCs from the diseased rats, indicating that T-cell-mediated immune responses may play a very important role for induction of these arthritides.6–9,15 However, the antigenic specificity of these T cells responsible for the induction and propagation of the diseases has not yet been defined in these models,17 though it has been reported that the arthritis-inducing T-cell clone could response to 65 000 MW mycobacterial heat-shock protein,18 type II collagen19 and cartilage proteoglycans.20

Our present study confirmed that an intravenous injection of LNCs from the diseased rats could transfer AA to the naive Lewis rats, all of which developed very severe arthritis with much earlier onset than that of AA. In spite of the finding that IFA pretreatment completely prevented the development of AA (Table 1), the IFA pretreated recipients could develop AA by passively transferred LNCs from AA rats. Furthermore, the LNCs from the IFA-pretreated donors could not prevent the development of AA in the CFA-challenged recipients. These findings suggested that the administration of IFA in Lewis rats can neither induce AA nor regulate the development of AA until these IFA-pretreated rats encounter some other additional stimuli, such as CFA. This hypothesis was supported in the present studies by the finding that the LNCs from the IFA-pretreated and subsequently CFA-challenged donors could induce less severe AA in only two out of eight naive recipients, whereas all the recipients which were challenged with CFA immediately after intravenous injection of these LNCs developed the disease, even with significantly less severity (P<0·05). Since AA is mediated by Th1 cells or Th1-type cytokines21,22 and polyclonal Th1 cells can transfer OIA to the naive DA rats,23 the present findings suggested in the context of the Th1/Th2 paradigm10 that Th1 cells responsible for inducing AA may be rich in LNCs from the diseased rats that are immunized with CFA and Th2 cells may be relatively rich in LNCs from the Lewis rats that are primed with IFA and subsequently challenged by CFA. In other words, the adjuvant-active vehicles such as IFA, hexadecane, squalane, methyl oleate and pristane could affect and deviate the Th1/Th2 balance of immune responses in host and subsequent administration of CFA could promote the propagation of Th2 cells rather than Th1 cells in these recipients through still undetermined mechanisms, eventually resulting in the prevention of the development of AA. The deviation of Th1/Th2 balance is somewhat similar to the concept of immune deviation proposed by Asherson.24 On the other hand, since IFA was able not only to induce arthritis,15 but also to prevent the development of AA in DA rats,25 it is possible that IFA and other vehicles described above induce non-specific inflammations, exert their adjuvant activities to potentiate and attenuate the reactivity of the host immune responses and then the subsequent administration of CFA may propagate the attenuated host immune responses to prevent AA in the Lewis rats, possibly through the cytokine networks.11 With regard to cytokines, it is well-known that Th1-type cytokines [interferon-γ, interleukin-2 (IL-2)] are essentially involved in the development of some autoimmune diseases (type 1 diabetes, EAE, RA, multiple sclerosis, etc.), whereas Th2-type cytokines (IL-4, IL-10, IL-13) are associated with other types of immune diseases (progressive systemic sclerosis, systemic lupus erythematosus, experimental autoimmune uveoretinitis, etc.).10,26 Furthermore, IL-6 is a multifunctional cytokine and plays an important role in induction of polyclonal B-cell abnormalities and autoimmune diseases.27,28 Therefore it is very important to elucidate the role of cytokines as well as of T cells for understanding the immunopathological mechanisms of autoimmune diseases.

Another possibility is that the IFA and other vehicles exerted their adjuvant activity as a stress to up-regulate the expression of endogenous self-heat-shock protein (hsp 60),29 and therefore the regulatory T cells which could respond to both mycobacterial hsp 65 and self-hsp 60 were activated to protect AA through some still uncertain mechanisms.30,31

In summary, the present studies showed that the pretreatment of various adjuvant active vehicles, such as IFA, hexadecane, squalane, methyl oleate, or pristane, could prevent the development of AA and this preventive effect could be passively transferred by LNCs, possibly through affect, and deviate the Th1/Th2 balance of immune responses, resulting in the Th1 bias responsible for production of arthritis, as in the DA rats,23 or in the Th2 bias responsible for preventing AA, as in Lewis rats. Alternatively, these immunologically active vehicles stimulate host tissue inflammation strongly enough to generate various cytokines and to make some endogenous self-antigens described above into strong immunogens or modified self-antigens, resulting in the regulation of autoimmune disease through induction or suppression. We are continuing to clone the T cells responsible for either induction or suppression of AA for future therapeutic models of human rheumatoid arthritis.

Acknowledgments

We thank Dr M. Morimoto of the Saga Medical School Animal Care Center for helping us with animal handling and Mr F. Muto of the Department of Pathology, Saga Medical School for preparing the histological specimens. We also thank Dr K. Ohki and Dr A. Kukita of the Department of Microbiology, Saga Medical School for their helpful comments and Ms I. Nanbu for her excellent secretarial assistance.

Abbreviations

AA

adjuvant arthritis

AIA

avridine-induced arthritis

CFA

complete Freund’s adjuvant

Con A

concanavalin A

EAE

experimental allergic encephalomyelitis

IFA

incomplete Freund’s adjuvant

IFN

interferon

IL

interleukin

ILNs

inguinal lymph nodes

LNCs

lymph node cells

Mt

Mycobacterium tuberculosis

OIA

oil-induced arthritis

PIA

pristane-induced arthritis

RA

rheumatoid arthritis

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