CD4⁺ but not CD8⁺ T cells revert the impaired emotional behavior of immunocompromised RAG-1-deficient mice.

An imbalanced immune system has long been known to influence a variety of mood disorders including anxiety, obsessive-compulsive disorders and depression. In this study, we sought to model the impact of an immunocompromised state on these emotional behaviors using RAG-1⁻/⁻ mice, which lack T and B cells. We also investigated the relative contribution of CD4⁺ or CD8⁺ T cells to these manifestations using RAG-1⁻/⁻/OT-II and RAG-1⁻/⁻/OT-I transgenic mice, respectively. Our results show that RAG-1⁻/⁻ mice present a significant increase in digging and marble-burying activities compared with wild-type mice. Surprisingly, these anxiety-like behaviors were significantly reverted in RAG-1⁻/⁻/OT-II but not RAG-1⁻/⁻/OT-I transgenic mice. Immunodepletion experiments with anti-CD4 or anti-CD8 in C57/BL6 mice or repopulation studies in RAG-1⁻/⁻ mice did not reproduce these findings. Microarray analysis of the brain of RAG-1⁻/⁻ and RAG-1⁻/⁻/OT-II mice revealed a significantly different gene fingerprint, with the latter being more similar to wild-type mice than the former. Further analysis revealed nine main signaling pathways as being significantly modulated in RAG-1⁻/⁻ compared with wild-type mice. Taken together, these results suggest that life-long rather than transient immunodeficient conditions influence the emotional behaviors in mice. Most interestingly, these effects seem to correlate with a specific absence of CD4⁺ rather than CD8⁺ T cells. Validation of these findings in man might provide new clues on the mechanism by which early life immune modulation might impact mood response in adults and provide a further link between immune and emotional well-being.

High density micromass cultures of a human chondrocyte cell line: a reliable assay system to reveal the modulatory functions of pharmacological agents.

Osteoarthritis is a highly prevalent and disabling disease for which we do not have a cure. The identification of suitable molecular targets is hindered by the lack of standardized, reproducible and convenient screening assays. Following extensive comparisons of a number of chondrocytic cell lines, culture conditions, and readouts, we have optimized an assay utilizing C-28/I2, a chondrocytic cell line cultured in high-density micromasses. Utilizing molecules with known effects on cartilage (e.g. IL-1ß, TGFß1, BMP-2), we have exploited this improved protocol to (i) evoke responses characteristic of primary chondrocytes; (ii) assess the pharmacodynamics of gene over-expression using non-viral expression vectors; (iii) establish the response profiles of known pharmacological treatments; and (iv) investigate their mechanisms of action. These data indicate that we have established a medium-throughput methodology for studying chondrocyte-specific cellular and molecular responses (from gene expression to rapid quantitative measurement of sulfated glycosaminoglycans by Alcian blue staining) that may enable the discovery of novel therapeutics for pharmacological modulation of chondrocyte activation in osteoarthritis.

The use of self-retained ureteral stents in the management of urologic complications in renal transplant recipients.

Nineteen self-retaining ureteral stents were used to manage postoperative ureteral obstruction and fistulas in 12 renal transplant recipients. In 3 patients with ureteral obstruction and 2 with a fistula placement of the self-retaining stents for 4 to 6 weeks allowed the complication to resolve. In 3 patients with ureteral obstruction placement of the self-retaining stents allowed for stabilization of the condition and reduction of immunosuppression therapy before an open surgical repair. In 6 patients self-retaining ureteral stents were used to protect the high risk anastomosis done at an open surgical repair of a complication. Placement of a self-retaining ureteral stent may be the best choice in the early management of ureteral obstruction and fistulas in transplant recipients.

Colon perforation in renal transplant patients.

Seven patients had perforated colonic diverticula 1 to 17 months after transplantation. Operation was performed immediately in four patients and from 4 days to 3 months later in three patients. Three patients are alive 9 to 36 months later. Two died of sepsis and two of myocardial infarction. Immediate operation with exclusion carries the best prognosis.

Clinical characteristics of the lethal cytomegalovirus infection following renal transplantation.

An ongoing prospective study of the role of viruses in renal transplant recipients has provided identification of two patterns of cytomegalovirus (CMV) infection. In both patterns, fever and leukopenia occur within 6 months after transplant. In addition, the benign form is characterized by renal biopsy evidence of rejection and brisk Antibody responses to CMV. The lethal syndrome runs a typical 4 week course, beginning with prostration, orthostatic hypotension, mild hypoxemia and progressing to severe pulmonary and hepatic dysfunction, muscle wasting, central nervous system depression, and death. antibody responses to CMV are minimal, and renal biopsy does not show rejection despite elevation of serum creatinine. At autopsy, CMV is found in lung, liver, kidney, gastrointestinal tract, and brain. Successful management of the potentially lethal kidney, gastrointestinal tract, and brain. Successful management of the potentially lethal CMV syndrome requires rapid clinical recognition and immediate reduction of immunosuppressive therapy. future prospects for control include development of a CMV vaccine and specific antiviral chemotherapy.

Immunopathological studies of the ruptured human renal allograft.

The immunopathology of five cases of spontaneous allograft rupture has been studied. All kidneys were edematous on exploration and routine histological sections showed interstitial edema and mononuclear cell infiltration characteristic of acute rejection. Immunofluorescence revealed, at most, scattered vascular deposition of IgM and mild mesangial C3 deposition. These findings are compared with findings in normal kidneys and kidneys which had been hyperacutely rejected. The normal kidney showed focal afferent arteriolar and proximal mesangial stalk deposition of C3 without IgM. The kidneys of patients with hyperacute rejection showed brilliant staining for fibrin and IgM in all arterial and arteriolar walls with lesser amounts of C3 and IgG; IgM and C3 were prominent in the glomerulus. These findings suggest that mechanisms other than circulating preformed antibodies are responsible for the pathogenesis of spontaneous allograft rupture.

Renal transplantation with blood supply by axillofemoral bypass graft.

An axillofemoral bypass was used to preserve a functioning renal allograft after excision of a mycotic abdominal aortic aneurysm in a diabetic patient. In the presence of continued immunosuppression the aortic wall infection progressed and the patient expired after rupture of the proximal aortic closure.

Successful management of miliary tuberculosis after renal transplantation.

Miliary tuberculosis is the most lethal form of tubercular disease. If dissemination of tubercle bacilli occurs without therapy, death is almost certain. The importance of establishing an etiologic diagnosis as promptly as possible in patients receiving immunosuppressive therapy is self-explanatory. The presence of a life-threatening infection in these patients requires aggressive antimicrobial therapy and discontinuation of the immunosuppressive drugs until the infectious process is under control; the presence of an impaired immunologic response is responsible for the life-threatening infection and the lack of an acute rejection reaction.

Late ureteropelvic necrosis after transplantation.

Total ureteropelvic necrosis of the transplanted kidney occurred more than one month after transplantation in 5 of 575 consecutive renal transplants performed at the University of Minnesota Hospital since 1963. Necrosis became evident long after normal renal function had been established. Histologic signs of rejection were minimal, but perinephric or periureteral hematomas were found in 3 of 5 patients: post-transplant acute tubular necorsis requiring hemodialysis occurred in all. The pathogenesis of this complication probably involves (1) a primary deficit of blood supply from the renal vessels to the pelvis and ureter, (2) a failure to develop a new ureteral blood supply because of surrounding hematoma, (3) early swelling of the ischemic ureter resulting in oliguria interpreted as acute tubular necrosis, (4) resolution of edema resulting in diuresis, and (5) late patchy ureteral necrosis and fistula formation due to ureteral ischemia.

Three year experience with bovine graft arteriovenous (A-V) fistulas in 100 patients.

On the basis of the preceding discussion and information, it is our conclusion that: 1. Bovine graft A-V fistuals can be created successfully in 87% of those patients who have had a failure of conventional fistuals. 2. Bovine graft A-V fistuals provide easy needle placement. 3. Bovine graft A-V fistuals give excellent access for effective hemodialysis. 4. Bovine graft A-V fistuals do not cause excessive bleeding at the puncture site. 5. Bovine graft A-V fistuals can be used immediately.

Cytomegalovirus: Clinical virological correlations in renal transplant recipients.

One-hundred thirty-two renal transplant recipients were systematically screened for viral infections and the findings correlated with the clinical course. One-hundred ten patients showed evidence of infection with herpesviruses and 89 patients showed laboratory evidence of infection with cytomegalovirus (CMV) uncomplicated by bacterial infections or technical complications. Patients without viral infections were usually asymptomatic. After recovery and development of anti-viral antibodies, most patients were asymptomatic despite the persistence of viral excretion in the urine. In contrast, the onset of viral infections were almost always accompanied by a significant clinical illness characterized by fever, leukopenia, and renal malfunction. Of 89 patients with cytomegalovirus infections, 83 survived at least three months. In these patients, the fever appeared to be self-limited and resolution of the fever was accompanied by increases in anti-CMV antibody. Renal biopsies demonstrated typical rejection reactions in all the biopsied patients and renal malfunction usually responded to anti-rejection treatment. Six of the 89 patients with CMV infections died within a month of viral isolation. These patients could be distinguished from those who recovered by a decreased or absent antibody response to the virus, suppressed lymphocyte responses to mitogen in autochthonous blood, and absent histologic evidence of rejection in the renal allografts. Thus, two paradoxical responses to CMV infections are seen in transplant patients: In the relatively immunocompetent patient, the infection is associated with renal allograft rejection, a prompt antibody response to the virus, and recovery. The severely immunosuppressed patient cannot make an antibody response, does not exhibit allograft rejection as a cause of renal malfunction, he may be further immunosuppressed by the viral infection, and is susceptible to sequential opportunistic infections leading to death.