Effect of Chronic Uremia on the Cell Surface Expression of B7 Family Costimulatory Molecules in an HLA-A2 Transgenic Mouse Model of Chronic Kidney Disease

Uremia due to chronic kidney disease (CKD) in humans is associated with immune dysfunction, increased susceptibility to infections, immune-activation–associated inflammation, and poor responses to vaccines. The pathophysiologic basis of these immune defects is hypothesized to be associated with a wide range of immunologic abnormalities, including an inability to sufficiently express the B7 family (B7-1, CD80; B7-2, CD86) of T-cell costimulatory molecules. However, testing the hypothesis that a state of chronic uremia contributes to attenuated expression of CD80 or CD86 has been difficult because few animal models faithfully recapitulate the immune defects observed in human CKD patients. We used a humanized mouse in a model of surgically induced renal failure and secondary chronic uremia to evaluate the effect of uremia on the expression of these markers. In a manner that resembles the changes observed in CKD patients, surgically induced CKD in mice resulted in decreased costimulatory CD86 expression compared with that in sham-operated controls. Immunodeficiency was functionally demonstrated in this mouse model by documenting an attenuated immune response to a cholera-toxin–based hepatitis B vaccine. This model will be useful for investigating the mechanisms involved in chronic uremia-associated immunodeficiency, poor response to vaccination, and problems associated with immunization of CKD patients.Abbreviations: CKD, chronic kidney disease; CT, cholera toxin; HBsAg, hepatitis B surface antigen; HLA, human leukocyte antigen; Th, T-helper cellThe B7 family of costimulatory molecules is critical in regulating adaptive immune responses and includes B7-1 (CD80) and B7-2 (CD86). These proteins are expressed on lymphoid and nonlymphoid cells and are part of a complex signaling network that includes chemokines, cytokines, adhesion molecules, and other immunoglobulin superfamily members. B7-1 and B7-2 deliver costimulatory or inhibitory signals through interaction with T-cell–associated CD28 or CTLA4 (CD152) molecules.^9,11,18,19 In particular, B7–CD28 ligation is necessary for a robust adaptive immune response to antigen that is presented in context with the MHC and T cell receptor complexes. Without B7 costimulation, T cell activation is compromised and the cell may enter an anergic state.¹³ In addition, active binding of B7, expressed by antigen-presenting cells, to CTLA4 that is expressed on responding T cells inhibits T-cell activation.^12,25 Therefore, any disease that alters the expression or function of B7 proteins has the potential to deregulate adaptive immunity.Uremia secondary to chronic kidney disease (CKD) is a disease that has been associated with reduced B7 expression and defects in innate and adaptive immunity in humans.⁹ Innate and adaptive immune dysfunction in CKD patients is associated with hyperinflammatory conditions, infections, atherosclerosis, and cardiovascular disease.^17,23 Some aspects of this dysfunction include impaired activation of T-lymphocytes, an increased T-helper cell (Th) Th1:Th2 ratio, lymphopenia, and impaired function of antigen-presenting cells.¹⁶ The function of antigen-presenting cells appears compromised in uremic patients through defective expression of B7-2 (CD86) on macrophages and dendritic cells.¹⁰ In contrast to that in human CKD patients, this pathology of reduced B7-2 expression has not previously been investigated in an animal model of uremia, and no model has been identified as having a defect in B7-2 expression.³Animal modeling of CKD is imperative to understand the pathogenesis of the disease. Furthermore, modeling will aid in the design and testing of therapeutic approaches. In the current study we examined the effect of surgically induced chronic uremia on the expression level of B7-1 and B7-2 in spleen cells of humanized B6.Cg-Tg(HLA-A/H2-D)2Enge/J transgenic mice (HLA-A2). We hypothesized that surgical induction of CKD and chronic uremia in HLA-A2 mice would result in the subsequent reduction of expression of B7-2 (that is, increased CD80:CD86 ratio) as compared with that of control mice that underwent sham surgery but did not become uremic. We show that the surgically induced chronic uremia protocol that we established results in a pathologic immune phenotype similar to that reported for immunodeficient humans with CKD, thus suggesting the utility of this approach as a new animal model of CKD.