Effects of Chemokine System Inactivation in Arthritis

The therapeutic goal in autoimmune diseases such as RA is to control disease, to establish remission, and eventually to cure. In theory, this goal can be achieved using either Ag-specific approaches, for example, elimination of self-reactive T cells (assuming that a finite number of key Ags can be identified as the target of the autoimmune process in RA), or the non-Ag-specific approaches, for example, blockade of cytokines as in the case of TNF-a neutralization. Currently, only the latter types of approaches have yielded clinical benefit, and it is in this category that approaches to block chemokines or receptors may be included. Despite their appeal in terms of effectiveness, non-Ag-specific approaches carry a higher risk of immunosuppression and opportunistic infections (48).

Although there is a myriad of ongoing clinical trials testing the effects of chemokine/receptor blockers in RA (Table 1), to date one cannot yet predict how many of the current targets will prove to be clinically effective. So for now, one must rely on results obtained with testing the effects of the blockade of the chemokine system in animal models of arthritis. Indeed, in several experimental models of arthritis, blockade of chemokines and their receptors has been shown to be effective (Tables 4 and 5). This broad array of potential targets is somehow encouraging, but also, it is reminiscent of the state of affairs in other model systems of autoimmune diseases such as type I diabetes (TID). In experimental TID, there has been a surprisingly high rate of effective research treatments that when administered early in the natural history of the disease had profound effects. However, in the clinical arena, the great majority of these research treatments have failed to demonstrate clinical benefit (49).

10.3.1. Study of Chemokines in Different Experimental Models of Arthritis

Different approaches have been used to probe the role of chemokines and their receptors in experimental models of arthritis; for instance, peptide antagonists or immunization of the host to promote the generation of "endogenous" neutralizing Abs via the use of chemokine plasmid DNA vaccination (Table 4 and Ref. 50), injection of neutralizing antibodies (Table 5), or mice that lack specific chemokine or chemokine receptors (Table 6).

In addition to CIA, there are several other models of arthritis that have also provided evidence for an important role of the chemokine system. Next, we will review some of the data available regarding the contribution of chemokines to disease pathogenesis in specific model systems beyond mere description of any given factor in the joints.

10.3.1.1 Adjuvant-Induced Arthritis

Rats develop arthritis that affects primarily diarthrodial, cartilaginous peripheral joints soon after injection of As emulsified in oil/adjuvants (51). Adjuvant-induced arthritis commonly presents with a chronic relapsing disease course. It has been shown that early in the disease course, there is an increase in the expression of neutrophil-chemoattracting chemokines KC/Gro-a/MIP-2 (CXCL1/CXCL2), while later in the disease course monocyte-attracting chemokine CCL2 is upregulated (52).

10.3.1.2. Collagen-Induced Arthritis

The incidence of arthritis induced in this model ranges from 40% to 80% depending on the method of induction, collagen preparation, and the adjuvants used for immunization (11,12,14,15,46,53). Because, most commonly, disease is induced in the DBA/1j background, and the majority of the knockout mice available are on the C57BL/6 or other backgrounds, little is known regarding the effects of germ-line inactivation of chemokines in CIA. As mentioned

Arthritis and Chemokine or Chemokine-Receptor Blockade Using Peptides/DNA

Target

Model of arthritis

Species

Peptide/DNA

Clinical effect

Potential mechanism/comments

Ref.

CCL3

(RANTES)

CXCL10 (IP-10)

AIA AIA AIA AIA CFA

CX3CL1 AIA

(Fractalkine)

MRL/lpr mice

Lewis rats

Lewis rats

Lewis rats

Lewis rats

MRL/lpr mice

Lewis rats

Lewis rats

Truncated CCL2, CCL2(9-76) (affect NH2-terminal) CCL2 naked

DNA CCL3 naked

DNA CCL4 naked

DNA CCL5 naked

DNA Truncated analogue of CXCL1, GRO-a(8-73). CXCL10 naked DNA

CX3CL1 naked DNA

Decrease cellular 56, 199

infiltration

I in acute and Production of self-specific 50

chronic phase antibody I in acute and Production of self-specific 50

chronic phase antibody I only in acute Production of self-specific 50

phase antibody

I in acute and Production of self-specific 50

chronic phase antibody I Less cell recruitment when 57

treated with anti-CXCLl + anti-CCL2 compared with anti-CCL2 alone I developing Production of self-specific 200 and ongoing antibody. Inhibits AIA leukocyte migration, alters the Thl/Th2 pattern.

<-» in chronic Similar arthritic score to 50 phase wild-type mice

CCRl CCR2 CCR5

CIA AIA CIA

Mice

A1B1, A4B7

Lewis rats INCB3344

DBA/1 mice

DBA/1 mice

Rhesus monkeys

A nonpeptide CCR5 antagonist, TAK-779. Also inhibits CXCR3. Met-RANTES. Also CCRl antagonist. SCH-X

CXCR2 CXCL8 or Rabbit N-(3-

LPS in (aminosulfonyl)

knee joint 4-chloro-2-

hydroxyphenyl) N'-( 2,3-dichlorophenyl)

urea

Reduced pannus formation 201

and bone resorption Inhibition of inflammation 92

and bone resorption Interfere with cell migration 45, 202 to joint lesions

Reduce incidence of 122, 203

disease in a dose-dependent manner. Suppressed acute-phase 204 reaction (reduction in C-reactive protein level and an altered antibody response toward type II collagen) Decrease cell recruitment 205 in synovial fluid

Model of

Potential

Target

arthritis

Species

Peptide/DNA

Clinical effect

mechanism/comments

Ref.

CXCR4

CIA

DBA/1 mice

AMD3100 (JM3100)

I

Reduce serum IL-6. No modified DTH. Inhibition of monocyte migration to CXCL12a.

206, 207

CIA in IFNyR

DBA/1

AMD3100

I

Inhibition of monocyte

208

null mice

mice

(JM3100)

migration to CXCL12a. Reduction of DTH response

I

to collagen type II.

CIA

DBA/1 mice

T140 analogue, 4F-benzoyl-TN14003.

NS. Decrease levels of serum anti-bovine CII IgG2a antibody.

209

Note: Effect: 4- decrease severity; T increase severity; «-» no effect.

AIA, adjuvant-induced arthritis; CFA, complete Freund's adjuvant; CIA, collagen-induced arthritis; DTH, delayed-type hypersensitivity; LPS, lipopolysaccharide.

Note: Effect: 4- decrease severity; T increase severity; «-» no effect.

AIA, adjuvant-induced arthritis; CFA, complete Freund's adjuvant; CIA, collagen-induced arthritis; DTH, delayed-type hypersensitivity; LPS, lipopolysaccharide.

Table 5

Arthritis and Results from the Use of Neutralizing Abs

Target

Model Species

Antibody

Clinical effect

Potential mechanism/comments

Ref.

CXCL5 (ENA-78)

AIA CAIA

CAIA

CIA AIA AIA

CIA CAIA

Lewis rats BALB/c mice BALB/c mice DBA/1 mice Lewis rats Lewis rats

DBA/1 mice BALB/c mice Lewis rats

Monoclonal

Polyclonal Polyclonal Polyclonal

Polyclonal

Polyclonal

I Decrease number of exudate

I macrophages

Reduced arthritis score

I Reduced arthritis score

I Decrease cell infiltration

I Decrease cell infiltration

I Decrease cell infiltration

I Decrease macrophages and neutrophils recruitment. Effective only when treatment was done before development of disease.

210 211

212 213 213

212 211

115, 214

Target

Model

Species

Antibody

Clinical effect

Potential mechanism/comments

Ref.

CXCL8

AIA

Lewis rats

Polyclonal

«—►

213

(KC, IL-8)

I

CX3CL1

CIA

DBA/1 mice

Hamster anti-mouse

Reduce infiltration of inflammatory

215

(Fractalkine)

FKN mAb (ICN

cells in synovium and bone

Pharmaceuticals)

erosion. It did not affect

production of serum anti-collagen

type II (CII) IgG or IFN-yby "

CH-stimulated splenic T cells.

CCR2

CIA

DBA/1 mice

Monoclonal

I

CCR2 blockade at early time points

89, 91

markedly improved histologic and

clinical signs of arthritis.

T

Late CCR2 blockade worsens clinical

and histologic outcome.

CCR5

CIA

DBA/1 mice

Monoclonal

«—►

46

Note: Clinical effect: 4- decrease severity; T increase severity; «-» no effect.

AIA, adjuvant-induced arthritis; CAIA, collagen Ab-induced arthritis; CIA, collagen-induced arthritis; DTH, delayed-type hypersensitivity.

Note: Clinical effect: 4- decrease severity; T increase severity; «-» no effect.

AIA, adjuvant-induced arthritis; CAIA, collagen Ab-induced arthritis; CIA, collagen-induced arthritis; DTH, delayed-type hypersensitivity.

Arthritis and Chemokine-Deficient and Chemokine Receptor-Deficient Mice

Gene Model of deficient Arthritis Strain

Clinical effect

Potential mechanism/comments

Ref.

13 S3

CAIA

C57BL/6

Lower SAP, TNF-a, and cell recruitment than wild type

CCR2

CIA

DBA/lj

T

Higher rheumatoid factor titers, enhanced T-cell activation, and monocyte/macrophage accumulation in the joints

43, 46

CAIA

DBA/lj

T

Prominent signs of chronic arthritis with pannus formation, and destructive bone and cartilage erosion, predominately of the distal joints

43, 46

Lyme arthritis

C3H/HeJ,

i—►

Similar to wild-type mice

217

Lyme arthritis

C57BL/6J

T and <-»

Temporal worsening

217

Mycobacterium

DBA/lj

T

Hyperplasia, synovitis, synovial cyst formation,

93

avium

fibroblast proliferation, and osteoid deposition.

infection

Presence of neutrophils in the interarticular space.

Higher levels of anti-CII Abs of the IgGl subtype.

CCR5

CIA

DBA/1

i—►

Similar to wild-type mice

43, 44, 46

CXCR2

Lyme arthritis

DBA

i—►

Similar to wild-type mice

217

Lyme arthritis

C3H/HeJ,

i

Inhibition of neutrophils to migrate to joint

217

Lyme arthritis

C57BL/6J

i

Inhibition of neutrophils to migrate to joint

217

Note: Clinical effect: 4- decrease severity; T increase severity; «-» no effect.

CAIA, collagen Ab-induced arthritis; CIA, collagen-induced arthritis; SAP, serum amyloid P-component.

Note: Clinical effect: 4- decrease severity; T increase severity; «-» no effect.

CAIA, collagen Ab-induced arthritis; CIA, collagen-induced arthritis; SAP, serum amyloid P-component.

earlier, DBA/1j CCR5 KO mice have a CIA phenotype that is indistinguishable from that of wild-type mice (43). Interestingly, inactivation of CCR2 in the DBA/1j mice is not associated with protection but rather with worsening of the disease phenotype (43). In the CIA model system, it has been shown that Ab blockade or chemical antagonism of several chemokines and chemokine receptors is highly effective in halting disease (Table 5).

MRL/lpr mice exhibit a complex and fascinating disease phenotype. The autosomal recessive mutation Ipr (lymphoproliferation) that affects the apoptosis-inducing system FAS-FASL leads to the spontaneous development of antibodies to native DNA, severe immune complex disease, and massive lymphadenopathy within the first few months of life (54). These mice spontaneously develop different autoimmune diseases such as systemic lupus erythema-tosus (SLE), Sjogren syndrome, and RA. These mice have circulating rheumatoid factor (RF) and develop histologic changes in their joints (55). Development of arthritis is commonly accelerated via intradermal injection of complete Freund's adjuvant (CFA). An extensive amount of data have demonstrated that peptide-mediated blockade of CCL2 prior to (56) or after disease development (57) significantly ameliorates arthritis development or disease severity, respectively.

10.3.1.4. Other Models of Arthritis

There is a paucity of information regarding the role of chemokines in the more recently introduced models of arthritis: (a) The KRN mouse model, an experimental system in which arthritis develops in mice on an NOD background, transgenic for a T-cell receptor recognizing an epitope of bovine RNase (KRN mice) (58,59). Notably, these mice produce Abs against glucose-6-phos-phate isomerase (GPI), and Abs induced acute arthritis when injected in recipient mice. (b) TNF-a-based genetic murine models of RA: These genetic models of arthritis are based on the transgenic expression of human or murine TNF-a -Tg (Transgenic) (60-63). These mice develop a chronic erosive polyarthritis with 100% phenotypic penetrance and timed disease onset. (c) Sakaguchi (SKG) mice (64,65), in response to fungal cell wall products, develop T cellmediated chronic autoimmune arthritis as a consequence of a mutation of the gene encoding a Src homology 2 (SH2) domain of Z-associated protein of 70 kd (ZAP-70), a key signal transduction molecule in T cells. This mutation impairs positive and negative selection of T cells in the thymus, leading to thymic production of arthritogenic T cells. Clinically, joint swelling begins in small joints of the digits, progressing in a symmetrical fashion to larger joints including wrists and ankles. Histologically, the swollen joints show severe synovitis with formation of pannus invading and eroding adjacent cartilage and subchondral bone. SKG mice develop extraarticular lesions, such as interstitial pneumonitis, vasculitides, and subcutaneous necrobiotic nodules not unlike rheumatoid nodules in RA. Serologically, they develop high titers of RF and autoantibodies specific for type II collagen. The role of chemokines in these models is being actively researched in the authors' laboratory.

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