Page 186 - Clinical Immunology_ Principles and Practice ( PDFDrive )

168 ParT ONE Principles of Immune Response

synthetase, a protein synthesis factor that is also able to induce Th1 immune response. Similar sets of inflammatory chemokines
DC chemotaxis, apparently by acting as an agonist at CCR5. Its are found in the mouse model as in human disease and appear
exact importance in promoting inflammation in myositis has in a strict temporal sequence.
not been established. Analysis of knockout mice has demonstrated that multiple
In general, T cell–dependent autoimmune diseases in human, chemokine receptors contribute to rejection in this model but
such as psoriasis, multiple sclerosis (MS), rheumatoid arthritis that there is a marked rank order: Cxcr3 > > Ccr5 > Ccr1 =
(RA), and type 1 diabetes mellitus, are associated with inflam- Cx3cr1 = Ccr2. Most impressively, rejection and graft arterio-
matory chemokines and tissue infiltration by T lymphocytes sclerosis do not occur if the recipient mouse, treated with a brief,
−/−
and monocytes expressing inflammatory chemokine receptors. subtherapeutic course of cyclosporine, is Cxcr3 or if the donor
−/−
In a mouse model of immune complex–induced arthritis, the heart is Cxcl10 . This identifies the CXCR3/CXCL10 axis as a
specific contributions of Ccr1, Cxcr2, Blt1 (a leukotriene B4 potential drug target. Neutralization of Cxcl9, a Cxcr3 ligand
receptor), and the C5a receptor have been dissected in detail in that appears later than Cxcl10, can also prolong cardiac allograft
joint venules at the level of adhesion and transendothelial migra- survival.
tion. A dominant negative antagonist of CCL2 inhibits arthritis In humans, CCR5 may be important in chronic kidney allograft
in the MRL-lpr mouse model of RA, suggesting a potential role rejection, since individuals homozygous for CCR5Δ32 are under-
for CCL2 and CCR2. Met-RANTES, a chemically modified variant represented among patients with this outcome in a large German
of CCL5 that blocks CCR1, CCR3, and CCR5, was shown to be kidney transplantation cohort.
beneficial in a collagen-induced arthritis model in DBA/I mice.
The relative importance of these in human disease is not Allergic Airway and Intestinal Disease
known. Drugs targeting CCR1 have failed in clinical trials in Chemokine receptors associated with asthma include CXCR2,
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RA. Likewise, although a gene association meta-analysis suggested CCR3, CCR4, and CCR8. CCR3 is present on eosinophils,
a protective effect for CCR5Δ32 in RA, the CCR5 antagonist basophils, mast cells, and some Th2 T cells. CCR4 and CCR8
maraviroc was ineffective in a clinical trial in patients with RA. identify airway T cells of allergen-challenged patients with atopic
Paradoxically, in some cases, blocking of chemokine receptors asthma.
can lead to increased inflammation, as shown for CCR1 and Ccr8 knockout mice have reduced allergic airway inflammation
CCR2 in mouse models of nephrotoxic nephritis and glomeru- in response to three different Th2-polarizing antigens: Schistosoma
lonephritis. This is associated with increased renal recruitment mansoni soluble egg antigen, ovalbumin, and cockroach antigen.
of CD4 and CD8 T cells, macrophages, and enhanced Th1 immune A role for the CCR3 axis in asthma has been supported by
responses. The mechanism remains unclear. Ccl11 neutralization in the guinea pig and Ccr3 gene knockout
in the mouse. The effect of Ccr3 knockout depends dramatically
Acute Neutrophil-Mediated Inflammatory Disorders on the specific method of sensitization and challenge because
Many neutrophil-mediated human diseases, including psoriasis, of complex and opposite effects on eosinophil and mast cell
−/−
gout, acute glomerulonephritis, acute respiratory distress syn- trafficking. Thus Ccr3 mice sensitized intraperitoneally have
drome, RA, and ischemia reperfusion injury, have been associated reduced eosinophil extravasation into the lung but increased
with the presence of CXCL8. Systemic administration of neutral- mast cell homing to the trachea. The net result is a paradoxical
izing anti-CXCL8 antibodies is protective in diverse models of increase in airway responsiveness to cholinergic stimulation. Mast
neutrophil-mediated acute inflammation in the rabbit (skin, cell mobilization is not seen after epicutaneous sensitization,
airway, pleura, glomeruli), providing proof-of-concept that and these animals have reduced airway eosinophilia on challenge
CXCL8 is a nonredundant mediator of innate immunity and and no increase in airway hyperresponsiveness.
−/−
acute pathological inflammation in these settings. CXCR2 Ccr6 mice have decreased allergic airway inflammation in
knockout mice are less susceptible to acute urate crystal-induced response to sensitization and challenge with cockroach antigen,
gouty synovitis. In addition, SB-265610, a nonpeptide small which is consistent with the induction of its ligand Ccl20 in this
−/−
molecule antagonist with exquisite selectivity for CXCR2, prevents model. Ccr6 mice are also protected from a mouse model of
neutrophil accumulation in the lungs of hyperoxia-exposed psoriasis, which is related to Ccr6 expression on monocytes and
newborn rats. Together, these results identify CXCL8 and its IL-17 expression in γδ T cells. Eosinophilic esophagitis has been
receptors as candidate drug targets for diseases mediated by associated with a CCL26 variant. Although there is no CCL26
acute neutrophilic inflammation. CXCR2 knockout mice also homologue in the mouse, other mouse CCR3 ligands have been
have shown delayed wound healing. Interestingly, studies of implicated in a mouse model of this disease.
Candida albicans and Pseudomonas aeruginosa infection in mice CCR9 is an attractive drug target in Crohn’s disease because
have suggested that the highly related neutrophil receptor Cxcr1 of its important role in T-cell homing to gut; however, a CCR9
does not mediate neutrophil recruitment into infected sites antagonist entered into clinical trials in this disease did not meet
but is, instead, involved in activation of antimicrobial effector the primary endpoint for efficacy.
mechanisms.
Cancer
Transplant Rejection Many chemokines and leukocyte subtypes have been detected
In the case of transplant rejection, the advantage over other in situ in tumors, and cancer cells have been shown to produce
animal models of human disease is that in both human and chemokines and express chemokine receptors. However, the role
animal situations, the time of antigenic challenge is precisely played by endogenous tumor-associated chemokines in recruiting
known. The most extensive analysis of the role of chemokines tumor-infiltrating lymphocytes and tumor-associated macro-
in transplant rejection has been carried out in an major histo- phages and in promoting an antitumor immune response has
compatibility complex (MHC) class I/II-mismatched cardiac not been clearly delineated. On the contrary, there are data from
allograft rejection model in the mouse, which is mediated by a mouse models suggesting that the overall effect may be to promote