B Cell Deficiency Confers Protection from Renal Ischemia Reperfusion Injury

Melissa J. Burne-Taney, Dolores B. Ascon, Frank Daniels, Lorraine Racusen, William Baldwin and Hamid Rabb
J Immunol September 15, 2003, 171 (6) 3210-3215; DOI: https://doi.org/10.4049/jimmunol.171.6.3210

Abstract

Recent data have demonstrated a role for CD4+ cells in the pathogenesis of renal ischemia reperfusion injury (IRI). Identifying engagement of adaptive immune cells in IRI suggests that the other major cell of the adaptive immune response, B cells, may also mediate renal IRI. An established model of renal IRI was used: 30 min of renal pedicle clamping was followed by reperfusion in B cell-deficient (μMT) and wild-type mice. Renal function was significantly improved in μMT mice compared with wild-type mice at 24, 48, and 72 h postischemia. μMT mice also had significantly reduced tubular injury. Both groups of mice had similar renal phagocyte infiltration postischemia assessed by myeloperoxidase levels and similar levels of CD4+ T cell infiltration postischemia. Peritubular complement C3d staining was also similar in both groups. To identify the contribution of cellular vs soluble mechanism of action, serum transfer into μMT mice partially restored ischemic phenotype, but B cell transfers did not. These data are the first demonstration of a pathogenic role for B cells in ischemic acute renal failure, with a serum factor as a potential underlying mechanism of action.

Renal ischemia reperfusion injury (IRI) 4 is a major cause of acute renal failure (ARF) and is associated with a high mortality rate in native kidneys and increased allograft rejection in the transplanted kidney. Despite significant advances over the last three decades, ARF remains a major clinical problem with unchanged mortality and morbidity rates (1, 2). The immunopathophysiological mechanisms of renal IRI are complex, involving multiple pathways (3, 4). Several studies have demonstrated that the blockade of leukocyte adhesion molecules (CD11/CD18, ICAM-1, selectins) protect the kidney in renal IRI, evidence of an important role of inflammation in the injury process (5, 6, 7). Although implicated in some studies, the role of the neutrophil in renal IRI is not as clear as originally thought and other leukocyte populations have been implicated in the disease pathogenesis (8). The T cell has recently been identified as an important modulator of renal IRI (9, 10). The T cell costimulatory molecule CD28 and its binding to the ligand B7-1 (CD80) also have an important role in renal IRI (11, 12). T cell-deficient mice (CD4/CD8 double knockout and nude (nu/nu) mice) were found to be markedly protected from renal IRI (9, 10). Substantial functional and structural kidney protection after ischemia was also found in mice deficient in CD4+ T cells. IFN-γ and the costimulatory surface receptor CD28 were found to participate in this effect (10). More recently, a protective role for the Th2 subset of CD4+ T cells has been identified using STAT6 knockout mice (13).

The mechanisms by which T cells modulate renal IRI are not known. There is abundant information that T and B cells can act in concert during immune responses (14, 15, 16, 17, 18). Given new evidence for the role of adaptive immunity in renal IRI, we therefore postulated that B cells could participate in the pathogenesis of renal IRI. To test this hypothesis, studies were conducted in B cell-deficient mice (μMT), which are incapable of developing peripheral mature B cells (19). B cell-deficient mice were found to be structurally and functionally protected from renal IRI as compared with wild-type mice, as well as having reduced mortality. To identify a possible mechanism involved in the protection from renal injury seen in the μMT mice, transfer experiments of B cells or serum from wild-type mice were investigated. Serum transfer, but not B cell transfer, restored the injury phenotype, indicating that a circulating factor mediates the protection seen in B cell-deficient mice. These findings could lead to novel therapeutic opportunities for renal IRI.

Materials and Methods

Mice

B cell-deficient mice, μMT (Igh-6tm1Cgn), and C57BL/6J wild-type littermate mice were purchased from The Jackson Laboratory (Bar Harbor, ME). B cell-deficient mice were generated by a targeted mutation of the membrane exons of the gene encoding the μ-chain constant region of IgM (19). The mice were maintained under specific pathogen-free conditions. All mice were male and 6–10 wk old. All experiments were performed in accordance with the Guide for the Care and Use Committee Guidelines.

Renal IRI model

An established model of renal IRI in mice was used (9). Briefly, mice were anesthetized with an i.p. injection of sodium pentobarbital (75 mg/kg). Following abdominal incisions, renal pedicles were bluntly dissected and a microvascular clamp (Roboz Surgical Instrument, Washington, DC) was placed on each renal pedicle for 30 min. During the procedure, animals were kept well hydrated with warm saline and at a constant temperature (∼37°C). After 30 min of ischemia, the clamps were removed, the wounds were sutured, and the animals were allowed to recover, with free access to food and water.

Assessment of renal function

Blood samples were obtained from the tail vein at 0 (preischemia), 24, 48, and 72 h postischemia. Serum creatinine levels (mg/dl) were measured to monitor renal function using the creatinine 557 kit (Sigma-Aldrich, St. Louis, MI) and an autoanalyzer (Roche, Basel, Switzerland).

Histology

At 72 h postischemia, kidneys were dissected from mice and tissue slices were fixed in 10% Formalin and processed for histology examination using standard techniques. Formalin tissue was embedded in paraffin and 4-μm sections were stained with H&E. These sections were examined in a blinded fashion by a renal pathologist and nephrologist. The percentage of histology changes in the cortex and medulla were scored using a semiquantitative scale designed to evaluate the degree of necrosis, cell loss, and necrotic casts on a five-point scale based on extent of involvement as follows: 0, normal kidney; 0.5, <10%; 1, 10–25%; 2, 25–50%; 3, 50–75%; and 4, 75–100%.

Neutrophil and macrophage detection using myeloperoxidase assay (MPO)

Neutrophil and macrophage infiltration postischemia were measured in mouse kidney at 0 (preischemia) and 72 h after renal IRI. Briefly, kidney samples were homogenized 1/20 (w/v) in ice-cold KPO4 buffer. Samples were spun at 17,000 × g for 30 min at 4°C, and pellets were washed and spun an additional two times. Then, 0.5% hexadecyltrimethylammonium bromide-10 mM EDTA was added to the remaining pellet (6/1). Suspensions were sonicated and freeze thawed three times, then incubated for 20 min at 4°C. After final centrifugation, supernatants were assayed for MPO. Changes in absorbance over 3.5 min were recorded at 460 nm. One unit of MPO activity was defined as change of absorbance of 1/min. Results were expressed as units of MPO per gram of protein, determined by bicinchoninic acid assay (Pierce, Rockford, IL). Recent data have demonstrated that the MPO assay detects infiltrating neutrophils as well as macrophages (20).

Immunohistochemistry

Kidney tissue sections (4 μm) were prepared on a cryostat and mounted on Fisher Superfrost Plus slides (Fisher Scientific, Pittsburgh, PA), fixed in ice-cold acetone for 1–2 min, and allowed to air dry. Sections were then blocked with 1/100 normal rabbit serum in PBS containing Vector Avidin DH (Vector Laboratories, Burlingame, CA). The primary Ab rat anti-mouse GK1.5 (rat anti-mouse CD4; American Type Culture Collection, Manassas, VA) was added to the sections. Sections were then incubated for 1 h at room temperature. An isotype control primary Ab was used as a background staining control. Sections were then rinsed in PBS and treated with 3% hydrogen peroxide in biotin (10 μg/L PBS). After washing steps in PBS, the slides were incubated with a biotin-conjugated rabbit anti-rat IgG secondary Ab (Vector Laboratories) for 35 min. After washing once again, sections were then incubated for 45 min in Vector Elite ABC (Vector Laboratories). Samples were washed and developed with 3-amino-9-ethyl-carbazole, counterstained with hematoxylin, and mounted with Glycergel (DAKO, Carpinteria, CA). The total number of positively stained cells was quantified in a blinded fashion in 10 high-power fields (×40 magnification).

Flow cytometry

Splenocytes were isolated according to standard techniques and treated with ammonium chloride/Tris buffer for 5 min to deplete RBC. Samples of 50 μl (106 cells) were incubated with Fc block (0.25 μg/106 cells) for 5 min and then stained using biotin-labeled rat anti-mouse CD19 (1D3) Ab and second-step reagent streptavidin-FITC for B cells and FITC-conjugated rat anti-mouse CD4 (H129.19) Ab and FITC-conjugated rat anti-mouse CD8b.2 (53-5.8) for T cells (BD PharMingen, San Diego, CA).

C3d staining

At the time of sacrifice, segments of kidneys were frozen in OCT. C3d was detected on frozen sections with directly fluorescein-conjugated rabbit Abs to C3d (DAKO). This reagent was produced to human C3d and cross-reacts with mouse C3d.

B cell and serum transfers

Spleens and lymph nodes (submandibular, axillary and inguinal) were collected from C57BL/6 wild-type mice. Centrifugation was performed and the RBC were removed by lysis in NH4Cl for 5 min. B cell enrichment was performed using B cell-negative selection columns according to the manufacturer’s specifications (Cellect-plus kits; Cytovax Biotechnologies, Alberta, Canada). Enriched B cells were then washed three times in HBSS to remove serum from the preparation. Approximately 70 × 106 enriched B cells were injected i.v. into each μMT mouse. IRI was induced in the mice 3 wk after transfer. The 3-wk time point was based on our preliminary studies in which earlier time points had less efficient B cell reconstitution.

Serum transfers were performed by collection of serum from wild-type mice. Blood samples were collected from wild-type mice and centrifuged to separate serum and RBC. Serum was collected and 0.5 ml was injected i.v. into each μMT mouse. Renal IRI was performed ∼20 h after injection of serum (21).

Determination of IgM and IgG by ELISA

Circulating levels of IgM and IgG in wild-type mice, B cell-deficient mice, B cell transfer recipients, and serum transfer recipients were assayed using an ELISA kit (Bethyl Laboratories, Montgomery, TX). Briefly, microtiter plates were coated with goat anti-mouse IgM and IgG at 100 μl/well and the plates were incubated for 1 h at room temperature. After washing, the plates were treated with blocking buffer (50 mM Tris and 0.1% BSA, pH 8) and incubated for 30 min. One hundred microliters of serum samples undiluted or diluted with sample diluent (50 mM Tris, 0.14 M NaCl, 1% BSA, and 0.05% Tween 20, pH 8) were added to plates. Serial dilutions of purified mouse IgM and IgG were used to generate standard curves. Following 1 h of incubation and washing steps, a HRP-conjugated anti-IgM or anti-IgG detection Ab was added. After addition of substrate solution, the reaction was stopped with 2 M H2SO4. The absorbance was measured at 450 nm on a Kinetic Microplate Reader model Vmax (Molecular Devices, Menlo Park, CA).

Statistical analysis

Data are expressed as mean ± SE. Statistical comparisons between groups were performed using Student’s t test. Mortality was compared using the Fisher exact test. Statistical significance was determined as a p < 0.05.

Results

B cell-deficient mice are protected from renal IRI

To examine the effect of B cell deficiency on renal dysfunction following IRI, we evaluated postischemic renal function in μMT mice. Fig. 1⇓ shows renal function in B cell-deficient mice after 30 min of renal IRI. Postischemic serum creatinine was significantly reduced in μMT mice compared with wild-type mice at 24 h (n = 19, 0.9 ± 0.1 vs n = 19, 2.7 ± 0.2, p < 0.05), 48 h (n = 19, 0.93 ± 0.1 vs n = 11, 2.6 ± 0.3, p < 0.05), and 72 h (n = 19, 0.73 ± 0.1 vs n = 10, 2.25 ± 0.3, p < 0.05). These data demonstrate that B cell-deficient mice are functionally protected from IRI compared with wild-type mice. Survival of B cell-deficient mice was also found to be significantly higher than survival in wild-type mice. B cell-deficient mice had a 100% survival following renal IRI at 72 h postischemia compared with 55% survival in wild-type mice (p < 0.05; Fig. 2⇓).

FIGURE 1.
FIGURE 1.

B cell-deficient mice are functionally protected from postischemic renal injury. Serum creatinine was significantly reduced at 24, 48, and 72 h (∗, p < 0.05) after renal IRI in B cell-deficient mice compared with wild-type mice. Serum creatinine was measured from tail blood samples after moderate ischemia (30 min of bilateral clamping).

FIGURE 2.
FIGURE 2.

Survival of B cell-deficient mice. The survival of B cell-deficient mice and wild-type mice was monitored at 24, 48, and 72 h postischemia. B cell-deficient mice showed 100% survival compared with wild-type mice (55%) (∗, p < 0.05).

Histology

To investigate the extent of tubular necrosis in B cell-deficient and wild-type mice, we examined kidney tissue at 72 h postischemia (Fig. 3⇓). The extent of epithelial necrosis in cortex and medulla measured as necrosis, cell loss, and necrotic casts is shown in Fig. 4⇓. Compared with normal kidney from wild-type mice (no IRI; Fig. 3⇓A), kidneys from wild-type mice at 72 h postischemia (Fig. 3⇓B) exhibit significant tubular injury characterized by extensive tubular epithelial necrosis and sloughing of epithelial cells into the tubular lumen. Many of the tubules were dilated and contained proteinaceous casts. The B cell-deficient mice (Fig. 3⇓C) show a significant protection from tubular damage in cortex and medulla compared with wild-type mice. Detailed anatomic semiquantitative assessment of kidney tissue confirmed that B cell-deficient mice demonstrated a protection from injury (Fig. 4⇓).

FIGURE 3.
FIGURE 3.

Histological assessment of tubular injury at 72 h postischemia by H&E staining. A, Normal wild-type mouse kidney (no IRI). B, Wild-type postischemic mouse kidney showing extensive tubular damage. C, B cell-deficient mice kidney shows structural protection from renal injury. Magnification, ×40.

FIGURE 4.
FIGURE 4.

Semiquantitative histological assessment of tubular injury at 72 h postischemia. PT, Proximal tubule; DT, distal tubule; NC(PT), necrotic cast in proximal tubule; NC(MR), necrotic cast in medullary rays; OM, outer stripe; IM, inner stripe; NC(OM), necrotic cast in outer stripe; NC(IM), necrotic cast in inner stripe (∗, p < 0.05).

Phagocyte infiltration

Neutrophil and macrophage infiltration into postischemic kidney were semiquantified with a myeloperoxidase assay. We observed a significant increase in MPO activity in wild-type mice at 72 h postischemia compared with baseline, with no significant difference in MPO activity between B cell-deficient and wild-type mice at 72 h postischemia (Fig. 5⇓).

FIGURE 5.
FIGURE 5.

Neutrophil and macrophage infiltration into the postischemic kidney using the MPO assay. After 72 h of ischemia, no significant difference was observed between wild-type mice and B cell-deficient mice.

CD4+ T cell infiltration into the postischemic kidney

In view of recent studies showing an important role of CD4+ T cells in renal IRI, we stained postischemic kidney tissue to evaluate the extent of infiltration of CD4+ T cells in B cell-deficient mice and wild-type mice. Previous data in this model demonstrates few CD4+ T cells infiltrating the kidney before 72 h postischemia (10). There was little difference in the number of CD4+ T cells in B cell-deficient mice (46 ± 8 cells per 10 high-power fields) and wild-type control mice (55 ± 3 cells per 10 high-power fields) postischemia. FACS analysis on splenic cells also demonstrated that wild type and μMT do not differ in their CD4+ and CD8+ population (data not shown).

C3d staining in the postischemic kidney

Since complement has been proposed to be important in renal IRI and is closely related to B cell function (22), we investigated whether complement deposition was different between wild type and μMT postischemia. Fig. 6⇓ shows postischemic kidneys stained with a FITC-labeled rabbit Ab to human C3d that cross-reacts with mouse C3d. In the absence of FITC-labeled Ab, yellow autofluorescent casts are visible in tubules from wild-type mice (Fig. 6⇓A). Fine linear staining for C3d in the tubular basement membrane (Fig. 6⇓, B and C, arrows) was similarly present in ischemic kidneys from wild-type and μMT mice (Fig. 6⇓, B and C, respectively). This staining was present in tubules that contained casts as well as those without casts.

FIGURE 6.
FIGURE 6.

C3d staining of postischemic kidney sections. In the absence of FITC-labeled Ab, yellow autofluorescent casts are visible in tubules from wild-type mice (A). Fine linear staining for C3d in the tubular basement membrane (arrows) was similarly present in ischemic kidneys from wild-type and μMT mice (B and C, respectively). This staining was present in tubules that contained casts as well as those without casts.

B cell and serum transfer experiments

B cell and serum transfers were performed to distinguish between cellular or soluble mechanisms whereby μMT mice are protected from renal IRI. Fig. 7⇓ shows serum creatinine values following renal IRI in wild-type mice, B cell transfer mice, serum transfer mice, and μMT mice. As found in the earlier described set of experiments, μMT mice were once again protected from renal IRI. B cell transfers were unable to restore the injury phenotype as evidenced by low serum creatinine levels when compared with wild-type mice. In contrast, serum transfer mice demonstrated a return of the injury phenotype with significantly increased serum creatinine levels when compared with those of μMT mice (p < 0.05). FACS analysis confirmed the presence of B cells after transfer in μMT mice (Fig. 8⇓).

FIGURE 7.
FIGURE 7.

Renal function following B cell or serum transfer. Serum creatinine was significantly reduced at 24, 48, and 72 h (∗, p < 0.05) after renal IRI in B cell-deficient mice compared with wild-type mice. B cell transfer mice were unable to return the injury phenotype as observed by serum creatinine levels similar to those of B cell-deficient mice. Serum transfers however were able to return the injury phenotype with significantly higher serum creatinine levels compared with those of B cell-deficient mice (#, p < 0.05).

FIGURE 8.
FIGURE 8.

FACS analysis confirming a return of B cells in the B cell transfer experiments. A, Wild-type mice show a normal population of B cells. B, μMT mice show no presence of B cells. C, B cell-transferred mice show a reconstitution of B cells.

IgG and IgM levels

The μMT mice contained undetectable levels of IgM and IgG in their plasma compared with wild-type control mice (Fig. 9⇓). IgG and IgM levels were also detected in both serum and B cell transfer experiments. Wild-type animals had the highest level of IgG and IgM. Neither serum or B cell transfers increase IgG or IgM levels to wild-type levels.

FIGURE 9.
FIGURE 9.

IgG and IgM levels in wild-type, B cell transfer, serum transfer, and μMT mice postischemia. B cell-deficient mice show undetectable levels of both IgG and IgM. Wild-type mice show normal levels of both IgG and IgM.

Discussion

This study identifies B cells as newly recognized participants in the pathophysiology of renal IRI. In the absence of B cells, the kidney is functionally and structurally protected postischemia compared with those of wild-type mice. Although the mechanisms underlying this effect may involve relationships with other leukocytes, our results suggest that changes in neutrophil or CD4+ T cell infiltration postischemia do not appear to be mediating this protective effect. Transfer experiments have identified a soluble serum factor as a likely mechanism by which B cell deficiency confers renal protection.

A number of studies have suggested that neutrophils are important mediators in renal IRI; however, this has not been confirmed in other studies (8). There is now emerging evidence that T cells participate in the full expression of injury after ischemia (10, 23). The current study was performed to test the hypothesis that the other major cell of the adaptive immune system, the B cell, could also participate in the pathogenesis of renal IRI. We studied the response of the well-characterized B cell-deficient mice (μMT) (19) in an established model of renal IRI characterized by sublethal renal injury. We found a marked protection in renal function postischemia compared with wild-type mice using serum creatinine, a reliable marker of the glomerular filtration rate in mice (24). We then evaluated histological changes postischemia in a blinded manner and found a parallel protection in the degree of tubular injury. Consistent with the functional and structural protection, the mortality in the B cell-deficient mice was significantly reduced compared with that of wild-type mice.

To begin to elucidate the potential mechanisms underlying the protection seen in the B cell-deficient mice, we measured MPO levels postischemia, which are reflective of infiltrating neutrophils and macrophages (20). Neutrophils and macrophages may be effector cells that ultimately mediate renal dysfunction by plugging up capillaries and releasing damaging free radicals and proteases. MPO levels were low at baseline in both wild-type and B cell-deficient mice and rose substantially postischemia. However, the rise in MPO was similar in both groups. In view of recent data identifying CD4+ T cells as modulators of renal IRI, we assessed CD4+ T cell infiltration into kidney, and this was similar in both the wild-type and B cell-deficient groups. Therefore, the influence of the infiltration of phagocytes and CD4+ T cells are unlikely to explain the protective effects we observed.

We initially embarked on studying B cells in renal IRI based on data that CD4+ T cells could modulate the course of renal injury (10). Studies in infectious diseases suggest an important role of B cells in the regulation of CD4+ T cells subset responses (14, 15, 16, 17, 18). Depending on the type of microbe, a specific Th1 or Th2 cytokine pattern is promoted (e.g., in malaria infections B cells play an essential role inducing a Th2 response (15, 16)). However, conflicting results in studies of B cells as APCs for T cell priming have been reported since the introduction of the B cell-deficient mice on the C57BL/6 background. It has been suggested that the absence of B cells in the μMT mice, which are B cell-deficient throughout their development, can affect the normal development and tissue organogenesis of lymph nodes (25). It is therefore possible that in renal IRI B cells could be involved in the polarization of the CD4+ T cell subsets, favoring a Th1 or Th2 response. Recent findings using STAT6 knockout mice have demonstrated a protective role of the Th2 phenotype of CD4+ T cells in renal IRI. In addition, the abnormal development of lymph nodes in the μMT mice might be a contributing factor for the protection observed in the μMT mice probably due to a defect of T cell function (25). Although there was no change in CD4+ T cell infiltration into kidney in this study between B cell-deficient and wild-type mice, we cannot rule out the possibility that a functional alteration in the CD4+ T cells led to protection from renal IRI in B cell-deficient mice.

Although this is the first demonstration for a role of the B cells in renal IRI, B cells have been postulated to be involved in the pathogenesis of IRI in skeletal muscle and intestine. B cells may mediate ischemic injury through the production of pathogenic IgM, which is deposited in the tissues and activates the classical pathway of complement (21, 26, 27). However, a recent study has shown that renal IRI can occur in RAG-1 mice that lack IgG or IgM Igs (28). Enhanced innate immunity in RAG-1 mice, much as enhanced NK activity, may have played a role in this finding. Furthermore, it has been reported that in renal IRI complement is activated by the alternative pathway (29) and that inhibition of C5a mediates renal IRI in the mouse kidney (30, 31, 32). These observations suggested that B cells or other soluble factors may be involved in the pathogenesis of renal IRI. B cells could also be orchestrating an effect on renal injury from a distant site, possibly through an interaction between B cells and T cells that may occur after recirculating to lymphoid organs of these cells or possibly via soluble cytokines.

To examine whether underlying mechanisms for the protection in B cell-deficient mice was through complement, we measured C3d deposition postischemia as a marker of the alternative and classical pathways of complement. We found that both wild-type and B cell-deficient mice had similar levels of complement deposition postischemia, suggesting that altered complement deposition was unlikely the mechanism of protection. We then sought to distinguish between a “cellular” or “soluble” mechanism of action. We therefore transferred either serum or purified B cells into μMT mice. We found that serum transfer was able to increase injury, but B cell transfers were not. This suggests the importance of a circulating factor, which may be an Ig in wild-type serum. The observation that B cell transfer did not restore injury does not totally exclude a cellular mechanism, as further enriched populations of B1 cells from peritoneum may be more important in IRI than total B cells (33).

Even though we found a marked protection afforded by B cell deficiency, it is important to note, similar to what has been found with ICAM-1 blockade in renal IRI, that there is a defined “window” of injury in which there is critical B cell involvement (34). More severe ischemic injury led to reduced differences in outcome between B cell-deficient and wild-type mice. These results, coupled with previous reports, provide evidence that components of the adaptive immune system are participating in the immediate injury response. These observations may help explain why increased ischemic injury to the organ is associated with enhanced acute and chronic rejection of renal allografts (35, 36). Our results implicate a novel and important role for B cells in the pathogenesis of renal IRI and open a new therapeutic window to treat ischemic ARF.

Acknowledgments

We thank Karen Fox-Talbot for performing outstanding immunofluorescent staining.

Footnotes

  • ↵1 M.J.B.-T. was supported by a National Kidney Foundation Postdoctoral Fellowship Award. H.R. was supported by National Institutes of Health Grant R01-DK54770. W.M.B. was supported by National Institutes of Health Grants P01-HL52315.

  • ↵2 M.J.B.-T. and D.B.A. contributed equally to this work.

  • ↵3 Address correspondence and reprint requests to Dr. Hamid Rabb, Johns Hopkins University School of Medicine, Ross Research Building, Room 970, 720 Rutland Avenue, Baltimore, MD 21205. E-mail address: hrabb1{at}jhmi.edu

  • ↵4 Abbreviations used in this paper: IRI, ischemia reperfusion injury; ARF, acute renal failure; MPO, myeloperoxidase.

  • Received November 2, 2002.
  • Accepted July 15, 2003.

References

  1. ↵
    Star, R. A.. 1998. Treatment of acute renal failure. Kidney Int. 54:1817.
    OpenUrlCrossRefPubMed
  2. ↵
    Thadhani, R., M. Pascual, J. V. Bonventre. 1996. Acute renal failure. N. Engl. J. Med. 334:1448.
    OpenUrlCrossRefPubMed
  3. ↵
    Okusa, M. D.. 2002. The inflammatory cascade in acute ischemic renal failure. Nephron 90:133.
    OpenUrlCrossRefPubMed
  4. ↵
    Rabb, H., R. Star. 2001. Inflammatory response and its consequences in acute renal failure. B. A. Molitoris, and W. F. Finn, eds. Acute Renal Failure: A Companion to Brenner and Rector’s The Kidney 89.-100. Saunders, Philadelphia.
  5. ↵
    Rabb, H., C. C. Mendiola, J. Dietz, S. Saba, T. B. Issekutz, F. Abanilla, J. V. Bonventre, G. Ramirez. 1994. Role of CD11a and CD11b in ischemic acute renal failure in rats. Am. J. Physiol. 267:F1052.
    OpenUrlPubMed
  6. ↵
    Kelly, K. J., W. W. Williams, R. B. Colvin, S. M. Meehan, T. A. Springer, J. C. Gutierrez-Ramos, J. V. Bonventre. 1996. Intercellular adhesion molecule-1-deficient mice are protected against ischemic renal injury. J. Clin. Invest. 97:1056.
    OpenUrlCrossRefPubMed
  7. ↵
    Nemoto, T., M. J. Burne, F. Daniels, M. P. O’Donnell, J. Crosson, K. Berens, A. C. Issekutz, B. Kasiske, W. Keane, H. Rabb. 2001. Small molecule selectin ligand inhibition improves outcome in ischemic acute renal failure. Kidney Int. 60:2205.
    OpenUrlCrossRefPubMed
  8. ↵
    Rabb, H., Y. M. O’Meara, P. Maderna, P. Coleman, H. R. Brady. 1997. Leukocytes, cell adhesion molecules and ischemic acute renal failure. Kidney Int. 51:1463.
    OpenUrlCrossRefPubMed
  9. ↵
    Rabb, H., F. Daniels, M. O’Donnell, M. Haq, S. R. Saba, W. Keane, W. W. Tang. 2002. Pathophysiological role of T lymphocytes in renal ischemia-reperfusion injury in mice. Am. J. Physiol. 279:F525.
    OpenUrl
  10. ↵
    Burne, M. J., F. Daniels, A. El Ghandour, S. Mauiyyedi, R. B. Colvin, M. P. O’Donnell, H. Rabb. 2001. Identification of the CD4+ T cell as a major pathogenic factor in ischemic acute renal failure. J. Clin. Invest. 108:1283.
    OpenUrlCrossRefPubMed
  11. ↵
    Takada, M., A. Chandraker, K. C. Nadeau, M. H. Sayegh, N. L. Tilney. 1997. The role of the B7 costimulatory pathway in experimental cold ischemia/reperfusion injury. J. Clin. Invest. 100:1199.
    OpenUrlCrossRefPubMed
  12. ↵
    De Greef, K. E., D. K. Ysebaert, S. Dauwe, V. Persy, S. R. Vercauteren, D. Mey, M. E. De Broe. 2001. Anti-B7-1 blocks mononuclear cell adherence in vasa recta after ischemia. Kidney Int. 60:1415.
    OpenUrlCrossRefPubMed
  13. ↵
    Yokota, N., M. Burne-Taney, L. Racusen, H. Rabb. 2003. Contrasting roles for STAT4 and STAT6 signal transduction pathways in murine renal ischemia-reperfusion injury. Am. J. Physiol. 285:F319.
    OpenUrlCrossRef
  14. ↵
    Bosio, C. M., D. Gardner, K. L. Elkins. 2000. Infection of B cell-deficient mice with CDC 1551, a clinical isolate of Mycobacterium tuberculosis: delay in dissemination and development of lung pathology. J. Immunol. 164:6417.
    OpenUrlAbstract/FREE Full Text
  15. ↵
    Langhorne, J., C. Cross, E. Seixas, C. Li, W. T. von der Weid. 1998. A role for B cells in the development of T cell helper function in a malaria infection in mice. Proc. Natl. Acad. Sci. USA 95:1730.
    OpenUrlAbstract/FREE Full Text
  16. ↵
    Taylor-Robinson, A. W., R. S. Phillips. 1996. Reconstitution of B-cell-depleted mice with B cells restores Th2-type immune responses during Plasmodium chabaudi infection. Infect. Immun. 64:366.
    OpenUrlAbstract/FREE Full Text
  17. ↵
    Homann, D., A. Tishon, D. P. Berger, W. O. Weigle, M. G. von Herrath, M. B. Oldstone. 1998. Evidence for an underlying CD4 helper and CD8 T-cell defect in B-cell-deficient mice: failure to clear persistent virus infection after adoptive immunotherapy with virus-specific memory cells from μMT/μMT mice. J. Virol. 72:9208.
    OpenUrlAbstract/FREE Full Text
  18. ↵
    Jankovic, D., A. W. Cheever, M. C. Kullberg, T. A. Wynn, G. Yap, P. Caspar, F. A. Lewis, R. Clynes, J. V. Ravetch, A. Sher. 1998. CD4+ T cell-mediated granulomatous pathology in schistosomiasis is downregulated by a B cell-dependent mechanism requiring Fc receptor signaling. J. Exp. Med. 187:619.
    OpenUrlAbstract/FREE Full Text
  19. ↵
    Kitamura, D., J. Roes, R. Kuhn, K. Rajewsky. 1991. A B cell-deficient mouse by targeted disruption of the membrane exon of the immunoglobulin μ chain gene. Nature 350:423.
    OpenUrlCrossRefPubMed
  20. ↵
    Ysebaert, D. K., K. E. De Greef, S. R. Vercauteren, M. Ghielli, G. A. Verpooten, E. J. Eyskens, M. E. De Broe. 2000. Identification and kinetics of leukocytes after severe ischaemia/reperfusion renal injury. Nephrol. Dial. Transplant. 15:1562.
    OpenUrlAbstract/FREE Full Text
  21. ↵
    Weiser, M. R., J. P. Williams, F. D. Moore, Jr, L. Kobzik, M. Ma, H. B. Hechtman, M. C. Carroll. 1996. Reperfusion injury of ischemic skeletal muscle is mediated by natural antibody and complement. J. Exp. Med. 183:2343.
    OpenUrlAbstract/FREE Full Text
  22. ↵
    Zhou, W., C. A. Farrar, K. Abe, J. R. Pratt, J. E. Marsh, Y. Wang, G. L. Stahl, S. H. Sacks. 2000. Predominant role for C5b-9 in renal ischemia/reperfusion injury. J. Clin. Invest. 105:1363.
    OpenUrlCrossRefPubMed
  23. ↵
    Zwacka, R. M., Y. Zhang, J. Halldorson, H. Schlossberg, L. Dudus, J. F. Engelhardt. 1997. CD4+ T-lymphocytes mediate ischemia/reperfusion-induced inflammatory responses in mouse liver. J. Clin. Invest. 100:279.
    OpenUrlCrossRefPubMed
  24. ↵
    O’Donnell, M. P., M. Burne, F. Daniels, H. Rabb. 2002. Utility and limitations of serum creatinine as a measure of renal function in experimental renal ischemia-reperfusion injury. Transplantation 73:1841.
    OpenUrlCrossRefPubMed
  25. ↵
    Rivera, A., C. C. Chen, N. Ron, J. P. Dougherty, Y. Ron. 2001. Role of B cells as antigen-presenting cells in vivo revisited: antigen-specific B cells are essential for T cell expansion in lymph nodes and for systemic T cell responses to low antigen concentrations. Int. Immunol. 13:1583.
    OpenUrlAbstract/FREE Full Text
  26. ↵
    Reid, R. R., S. Woodcock, A. P. Prodeus, J. Austen, L. Kobzik, H. Hechtman, F. D. Moore, Jr, M. C. Carroll. 2000. The role of complement receptors CD21/CD35 in positive selection of B-1 cells. Curr. Top. Microbiol. Immunol. 252:57.
    OpenUrlPubMed
  27. ↵
    Williams, J. P., T. T. Pechet, M. R. Weiser, R. Reid, L. Kobzik, F. D. Moore, Jr, M. C. Carroll, H. B. Hechtman. 1999. Intestinal reperfusion injury is mediated by IgM and complement. J. Appl. Physiol. 86:938.
    OpenUrlAbstract/FREE Full Text
  28. ↵
    Park, P., M. Haas, P. N. Cunningham, L. Bao, J. J. Alexander, R. J. Quigg. 2000. Injury in renal ischemia-reperfusion is independent from immunoglobulins and T lymphocytes. Am. J. Physiol. 282:F352.
    OpenUrl
  29. ↵
    Thurman, J. M., D. Ljubanovic, C. Edelstein, G. S. Gilkeson, V. M. Holers. 2003. Lack of a functional alternative complement pathway ameliorates ischemic acute renal failure in mice. J. Immunol. 170:1517.
    OpenUrlAbstract/FREE Full Text
  30. ↵
    de Vries, B., J. Kohl, W. K. Leclercq, T. G. Wolfs, A. A. van Bijnen, P. Heeringa, W. A. Buurman. 2003. Complement factor C5a mediates renal ischemia-reperfusion injury independent from neutrophils. J. Immunol. 170:3883.
    OpenUrlAbstract/FREE Full Text
  31. ↵
    de Vries, B., R. A. Matthijsen, T. G. Wolfs, A. A. van Bijnen, P. Heeringa, W. A. Buurman. 2003. Inhibition of complement factor C5 protects against renal ischemia-reperfusion injury: inhibition of late apoptosis and inflammation. Transplantation 75:375.
    OpenUrlCrossRefPubMed
  32. ↵
    Arumugam, T. V., I. A. Shiels, A. J. Strachan, G. Abbenante, D. P. Fairlie, S. M. Taylor. 2003. A small molecule C5a receptor antagonist protects kidneys from ischemia/reperfusion injury in rats. Kidney Int. 63:134.
    OpenUrlCrossRefPubMed
  33. ↵
    Reid, R. R., S. Woodcock, A. Shimabukuro-Vornhagen, W. G. Austen, Jr, L. Kobzik, M. Zhang, H. B. Hechtman, F. D. Moore, Jr, M. C. Carroll. 2002. Functional activity of natural antibody is altered in Cr2-deficient mice. J. Immunol. 169:5433.
    OpenUrlAbstract/FREE Full Text
  34. ↵
    Rabb, H., C. C. Mendiola, S. R. Saba, J. R. Dietz, C. W. Smith, J. V. Bonventre, G. Ramirez. 1995. Antibodies to ICAM-1 protect kidneys in severe ischemic reperfusion injury. Biochem. Biophys. Res. Commun. 211:67.
    OpenUrlCrossRefPubMed
  35. ↵
    Tilney, N. L., R. D. Guttmann. 1997. Effects of initial ischemia/reperfusion injury on the transplanted kidney. Transplantation 64:945.
    OpenUrlCrossRefPubMed
  36. ↵
    Terasaki, P. I., J. M. Cecka, D. W. Gjertson, S. Takemoto. 1995. High survival rates of kidney transplants from spousal and living unrelated donors. N. Engl. J. Med. 333:333.
    OpenUrlCrossRefPubMed
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