Induction of Transplantation Tolerance With MAb

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1. Animals: most animal studies have been performed in mice, although rats and nonhuman primates have been tolerized to foreign antigens and transplants with MAb. Transplant rejection or tolerance does not depend exclusively on the degree of mismatch between host and donor. Different strains of mice exhibit distinct behavior concerning the capacity to reject or become tolerant to transplants (27,28), which may be further modulated upon exposure to infectious microorganisms (see Note 1). In general, the hierarchy of strains, from the easiest to toler-izeate to the most difficult, is as follows: C3H, CBA/Ca, DBA/2, BALB/c, and C57Bl/6. Apparently, these properties are not primarily due to the MHC molecules present in each strain. For instance, B10.BR mice, expressing identical MHC molecules to CBA/CA mice, are as difficult to tolerize as C57Bl/6 with whom they share only minor antigens (27). The genetic basis of strain variability is still unknown.

Several studies have used T-cell receptor (TCR) transgenic animals, where all T cells share the same TCR. Even in these mice, it has been possible to use MAb, such as nondepleting CD4 or CD 154, to induce a state of dominant tolerance where the de novo peripheral generation of Treg cells can be demonstrated (29). It should be noted that prior to tolerization, these TCR-transgenic animals have no demonstrable CD4+CD25+Foxp3+ Treg cells.

2. Transplanted tissue: the capacity to accept a transplant also depends on the graft itself. In general, the greater the genetic disparity between donor and recipient, the more difficult it becomes to prevent rejection. The donor strain itself may also contribute to different outcomes in terms of tolerance. For example, BALB/c grafts are harder to tolerize than C57Bl/6 grafts in CBA/Ca recipients (23,30). In addition, different organs have been shown to have distinct requirements for succumbing to tolerance induction (31,32). Vascularized grafts are, in general, more easily accepted than nonvascularized grafts, such as skin. Acceptance of the liver is relatively easy to achieve, with many different liver allografts being spontaneously accepted by permissive strains without any treatment (33). Kidney allografts are also occasionally spontaneously accepted in rodents, although not as consistently as liver (32). In contrast, pancreatic islets and heart allografts are usually rejected in the absence of therapeutic intervention. It should be noted that in diabetic animals, such as nonobese diabetic (NOD) mice, it is more difficult to induce tolerance to islet allografts presumably because a primed autoimmune response must be overcome in addition to the allogeneic barrier (34,35). The rejection of small intestine seems to be more vigorous than the above mentioned organs (32,36). However, skin grafts are even more difficult to tolerize as some treatments, capable of preventing rejection of heart allografts, are ineffective in inducing long-term survival of skin allografts (37-40). It is known that both CD4+ and CD8+ T cells can contribute to skin graft rejection, with each population capable of rejecting grafts independently (29).

3. Antibodies: several antibodies and fusion proteins have been shown to be effective at inducing dominant transplantation tolerance, either on their own or in combination (see Table 1). It is interesting to note that virtually all MAb able to induce peripheral tolerance, target molecules involved in the formation of the immune synapse: the coreceptor molecules CD3, CD4, and CD8 (10,41); CD45RB (42); the costimulatory molecules CD154 and CD28 (43-45); and the adhesion molecules leukocyte function-associated antigen 1 and intercellular adhesion molecule-1 (9,46). It is thus possible that tolerance induction requires T-cell activation under suboptimal conditions, i.e., in the presence of reagents that interfere with efficient T-cell activation, although this does not extend to conventional immunosuppressive agents (see Note 2) (47).

2.2. Induction of Tolerance With MAb in Autoimmunity

1. Animals: the use of MAb to restore the state of dominant regulation has been tested in several animal models of autoimmune and immune-inflammatory disease. Some of the most common examples are listed in Table 2. Such animal models can be divided into three broad categories: (1) animals developing the disease spontaneously, (2) animals where the disease is induced experimentally, and (3) TCR-transgenic animals where most or all the T cells are specific for a self-antigen. It should be noted that some animals, initially described as developing an autoimmune disease spontaneously, were later found to develop the disease following an environmental challenge. This is the case for SKG mice, carrying a mutation of the ZAP-70 gene, that develop chronic autoimmune arthritis with features closely resembling rheumatoid arthritis (RA) (48). In spite of initial reports suggesting that autoimmune arthritis was spontaneous, it was recently shown that the disease is triggered by Dectin-1 agonists such as zymosan (49). It is also important to note that the immune systems of most animals used in animal models of autoimmune disease behave as lymphopenic (see Note 3) (50). Some of the most common animal models of autoimmune pathology are as follows:

Autoimmune diabetes: NOD mice spontaneously develop insulin-dependent diabetes and are a model of type I diabetes mellitus. Disease in these animals, as in humans, appears to be of autoimmune aetiology that is heavily influenced by both genetics and environment (51,52). The similarity between diabetes in the NOD mice and humans is extensive, including the influence of sex on the incidence of disease: whereas about 80% of female mice at 6 mo of age are diabetic, only 20% of males develop the disease (53). BB rats also develop autoimmune diabetes spontaneously but, as in humans, the disease incidence is similar in both sexes and not affected by gonadectomy or androgen administration (54). The immune system of these rats is

Table 2

Animal Models of Autoimmune Diseases

Associated human disease

Reference

Mouse models Spontaneous NOD

T/R- (TCR transgenic to MBP) Induced

DBA/1 + Type II collagen in IFA SKG + Dectin-1 agonists BALB/c + Spinal cord homogenate in CFA SJL + PLP in CFA SLJ + Thyroglobulin in CFA Rat models Spontaneous BB/wor

Komeda diabetes-prone (KDP) Lewis (LEW.1AR1/Ztm) Induced Lewis + retinal pigment epithelium-specific 65-kDa protein peptides Lewis + MBP in CFA Wistar + MBP in CFA Wistar + testis homogenates

Type l diabetes

RA RA MS

Autoimmune thyroiditis

Type l diabetes Type l diabetes Type l diabetes

Autoimmune uveitis

MS MS

Autoimmune orchitis

56-58 48,49 64

61 118

120 121

123 32

CFA, complete Freund's adjuvant; IBD, inflammatory bowel disease; IFA, incomplete Freund's adjuvant; MBP, myelin basic protein; MS, multiple sclerosis; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus.

severely lymphopenic. Another rat model of diabetes is the LEW.1WR1 rat (RT1Uu/a) where the disease occurs spontaneously with a cumulative frequency of approx 2% at a median age of 59 d. Both sexes are affected, and islets of acutely diabetic rats are devoid of P cells whereas a and 8 cell populations are spared (55).

RA: the most commonly used animal models of autoimmune arthritis are mice and rats in which the disease is induced with type II collagen and incomplete Freund's adjuvant (56-58). In these cases, the disease usually affects larger joints of the limbs and is self-limited. K/BxN mice spontaneously develop a progressive joint-specific autoimmune disease between 3 and 5 wk of age. Pathology of disease in K/BxN mice is similar to human RA, with pannus formation, synovial hyperplasia, increased synovial fluid volume, and chaotic remodelling of cartilage and bone in the distal joints in the later stages (59,60). SKG mice, harboring T cells more resistant to TCR stimulation, also develop chronic autoimmune arthritis. Although disease in K/BxN mice is mediated by antibodies and can be adoptively transferred to healthy recipients by transferring the serum, in SKG mice arthritogenic T cells are sufficient to cause the disease as their adoptive transfer into lymphocyte-deficient hosts triggers autoimmune arthritis (48).

Multiple sclerosis: EAE is characterized by T cell-mediated destruction of the myelin sheath in the central nervous system. Myelin basic protein, myelin/oligo-dendrocyte glycoprotein, and proteolipid apoproteins when administered with adjuvant to mice or rats can induce autoreactive T cells that cause the disease (61-63). The same outcome has been reported following the administration of syngeneic mouse spinal cord homogenate in complete Freund's adjuvant (64). TCR transgenic mice in the RAG/- background, in which all T cells express a TCR directed to a myelin protein, spontaneously develop EAE with 100% incidence at 8 mo (65,66). Interestingly, the disease is abrogated by the presence of additional CD4+ T cells from wild-type syngeneic mice (67,68).

Systemic lupus erythematosus (SLE): MRL/lpr mice spontaneously develop a disease similar to SLE, because of defective apoptosis of activated B cells as the mice are deficient in Fas/FasL (69). Other mouse strains, such as the NZB x NZW and the BXSB, also develop a SLE-like syndrome that appears to be influenced by multiple genes (69).

2. Antibodies: several MAb have been tested for the treatment of autoimmune diseases. In many cases such MAb do not aim to restore tolerance but rather to control the inflammatory process (such as the anti-tumor necrosis factor a or the anti-interleukin-1 MAb) (70), or induce immunosuppression by elimination of pathogenic lymphocyte populations (such as T-cell depletion with CAMPATH or B-cell depletion with anti-CD20) (71,72). However, tolerogenic MAb have also been reported to have a beneficial effect on the prevention or treatment of autoimmune pathology, although in many cases the true re-establishment of dominant self-tolerance based on T-cell regulation remains to be confirmed (see Table 3).

CD3: therapy with nonmitogenic CD3 MAb has been shown to prevent and revert type 1 diabetes in NOD mice and in virus-induced autoimmune diabetes (73-75). Different from most other tolerogenic MAb, anti-CD3 seems to be more effective if used after the onset of disease, apparently because activated T cells are the main targets of this treatment (74). In autoimmune arthritis the use of this antibody was not shown to be as effective as in type 1 diabetes, but in both systems, treatment causes a reduction in serum interferon-y and an increase in interleukin-4, interpreted as deviation to a Th2 response (76). Anti-CD3 MAb were also shown to lead to an increase in Treg cells able to suppress diabetogenic T cells and maintain a state of dominant tolerance (26,77).

CD4: following initial reports showing a beneficial effect of anti-CD4 on the treatment of EAE in rats (5), it has been shown that nondepleting CD4 MAb can

Table 3

Targets of Therapeutic MAb in Experimental Autoimmune Diseases

Table 3

Targets of Therapeutic MAb in Experimental Autoimmune Diseases

MAb

Animal/disease

Outcome

Reference

CD2

Lewis rats (EAM)

Prevents onset

125

Lewis rats (EAE)

Prevents onset

126

BB/wor rats (type 1

Prevents onset

119

diabetes)

CD3

NOD mouse (Type 1 diabetes)

Ameliorates established disease

26,73-75

DBA/1 mouse (CIA)

Delayed onset, reduced severity

76

CD4

NOD mouse (Type 1 diabetes)

Prevents onset

78-81

NZB/NZW mouse

Ameliorates established disease

127

(murine SLE)

DBA/l (CIA)

Prevents onset and ameliorates established disease

86-87

CD30L

NOD mouse (type 1 diabetes)

Prevents onset

128

OX40L

SJL mouse (EAE)

Ameliorates established disease

61

C.B-17 SCID (IBD)

Ameliorates established disease

138

CTLA4-Ig

BALB/c mouse (EAE)

Ameliorates established disease

64

NZB/NZW mouse

Prevents onset

129-132

(SLE)

BXSB mouse (SLE)

Delayed onset, reduced severity

133

CD154

Marmoset monkey (EAE)

Prevents onset

134

B6/A (C57BL/6xA/J)

Prevents onset

98

(AOD)

B10.BR mouse

Ameliorates established disease

135

(EAU)

SJL mouse (EAT)

Less severity

118

NZB/NZW mouse

Prevents onset

136-139

(SLE)

CD40

Marmoset monkey (EAE)

Prevents onset

140

CD137

DBA/1 (CIA)

Prevents onset

141

NZB/NZW mouse

Ameliorates established disease

142

(SLE)

C.B-17 SCID (IBD)

Ameliorates established disease

143,144

C57BL/6 (EAE)

Ameliorates established disease

(Continued)

Table 3 (Continued)

MAb

Animal/disease

Outcome

Reference

LFA-1

NOD mouse (Type 1

Prevents onset

145

diabetes)

EAE, experimental allergic encephalomyelitis; EAM, experimental autoimmune myelitis; AOD, autoimmune ovary disease; CIA, collagen-induced arthritis; EAU, experimental autoimmune uveoretinitis; IBD, inflammatory bowel disease; MS, multiple sclerosis; SLE, systemic lupus erythematosus.

EAE, experimental allergic encephalomyelitis; EAM, experimental autoimmune myelitis; AOD, autoimmune ovary disease; CIA, collagen-induced arthritis; EAU, experimental autoimmune uveoretinitis; IBD, inflammatory bowel disease; MS, multiple sclerosis; SLE, systemic lupus erythematosus.

prevent the onset of diabetes in NOD mice, as well as preventing pancreatic islet damage in recently established disease, with the animals tolerating islet transplants from prediabetic syngeneic donors or even islet allografts (78-82). The same MAb have also been shown to prevent the onset of experimental autoimmune arthritis as well as to ameliorate overt arthritis (83-85).

Several other MAb, such as the ones targeting CD154, CTLA4-Ig, and CD134L, have been shown effective in preventing or treating several experimental autoimmune diseases (see Table 3).

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Arthritis Joint Pain

Arthritis Joint Pain

Arthritis is a general term which is commonly associated with a number of painful conditions affecting the joints and bones. The term arthritis literally translates to joint inflammation.

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