Bilateral native nephrectomy improves renal isograft function in rats

Bilateral native nephrectomy improves renal isograft function in rats. Bilateral native nephrectomy has been suggested to improve renal allograft survival in man. This effect may be most prominent in patients experiencing acute tubular necrosis following transplantation. Thus, native kidneys may alter the course of ischemic acute tubular necrosis in the transplanted kidney. In the present studies, we utilized an experimental model of syngeneic transplantation in which rejection does not occur. We studied Lewis rat renal isografts transplanted into littermates following sham, unilateral or bilateral native nephrectomy. In a fourth group of rats, we evaluated the importance of native kidney excretory function by studying isografts transplanted into littermates with bilaterally obstructed native kidneys. Renal blood flow and excretory function were measured in vivo, eight days following transplantation. Renal excretory function of isografts transplanted into animals following bilateral native nephrectomy was similar to normal nontrans-planted Lewis kidneys. The presence of either one or both functioning native kidneys significantly reduced isograft inulin clearance, PAH clearance, and blood flow. However, when isografts were transplanted into Lewis rats with bilaterally obstructed native kidneys, renal isograft inulin clearance and blood flow were not significantly impaired Non-transplanted kidneys demonstrated “functional hypertrophy” following contralateral nephrectomy, with glomerular filtration rate and renal blood flow increasing by approximately 50%. In contrast, isograft glomerular filtration rate in animals following bilateral native nephrectomy was equivalent to that of single kidneys from normal animals with both kidneys in situ. However, renal blood flow of isografts from these animals increased to the same level as nontransplanted Lewis kidneys following contralateral nephrectomy. Histological examination of isografts from animals with functioning native kidneys in situ demonstrated extensive disruption of normal renal architecture with tubular and interstitial injury. This was in marked contrast to the appearance of Lewis–Brown Norway allografts, to isografts from animals following bilateral native nephrectomy, and to isografts from animals with bilaterally obstructed native kidneys. In Lewis–Brown Norway allografts, there was evidence of rejection with active inflammatory cell infiltration, arteriolitis and venulitis. In isografts from animals following bilateral native nephrectomy or with bilaterally obstructed native kidneys, renal architecture was normal. Thus, the detrimental effect of native kidneys on isograft function may be related to impaired recovery from ischemia or potentiation of ischemic injury which occurs during the transplantation procedure

Nonintegrating Lentiviral Vector-Based Vaccine Efficiently Induces Functional and Persistent CD8+ T Cell Responses in Mice

CD8+ T cells are an essential component of an effective host immune response to tumors and viral infections. Genetic immunization is particularly suitable for inducing CTL responses, because the encoded proteins enter the MHC class I processing pathway through either transgene expression or cross-presentation. In order to compare the efficiency and persistence of immune response induced by genetic vaccines, BALB/c mice were immunized either twice intramuscularly with DNA plasmid expressing a codon-optimized HIV-1 gp120 Envelope sequence together with murine GM-CSF sequence or with a single immunization using an integrase defective lentiviral vector (IDLV) expressing the same proteins. Results strongly indicated that the schedule based on IDLV vaccine was more efficient in inducing specific immune response, as evaluated three months after the last immunization by IFNγ ELISPOT in both splenocytes and bone marrow- (BM-) derived cells, chromium release assay in splenocytes, and antibody detection in sera. In addition, IDLV immunization induced high frequency of polyfunctional CD8+ T cells able to simultaneously produce IFNγ, TNFα, and IL2

Chronic rejection of mouse kidney allografts

Chronic rejection of mouse kidney allografts.BackgroundChronic renal allograft rejection is the leading cause of late graft failure. However, its pathogenesis has not been defined.MethodsTo explore the pathogenesis of chronic rejection, we studied a mouse model of kidney transplantation and examined the effects of altering the expression of donor major histocompatibility complex (MHC) antigens on the development of chronic rejection.ResultsWe found that long-surviving mouse kidney allografts develop pathological abnormalities that resemble chronic rejection in humans. Furthermore, the absence of MHC class I or class II antigens did not prevent the loss of graft function nor alter the pathological characteristics of chronic rejection. Expression of transforming growth factor-β (TGF-β), a pleiotropic cytokine suggested to play a role in chronic rejection, was markedly enhanced in control allografts compared with isografts. However, TGF-β up-regulation was significantly blunted in MHC-deficient grafts. Nonetheless, these differences in TGF-β expression did not affect the character of chronic rejection, including intrarenal accumulation of collagens.ConclusionsReduced expression of either class I or II direct allorecognition pathways is insufficient to prevent the development of chronic rejection, despite a reduction in the levels of TGF-β expressed in the allograft. This suggests that the severity of chronic rejection is independent of the level of MHC disparity between donor and recipient and the level of TGF-β expression within the allograft

The imperative to invest in science has never been greater

In order to sustain and improve the health of Americans, to ensure our ability to overcome new health challenges, and to realize the economic benefits of a vigorous scientific economy, we encourage our government to implement three actions. First, establish predictable, managed growth in the US scientific enterprise by establishing a sustainable and predictable real annual increase in science funding. This will require additional investments in the proven NIH-university partnership to maintain our world-leading position in biomedical science. Second, preserve the current cadre of well-trained junior scientists, including physician-scientists, and maintain a pipeline of young scientists motivated to innovate and improve health. Third, analyze changing health needs and priorities for health science–related investments in order to address ongoing shifts in population demographics and diseases, opportunities for improved prevention or treatment, and the availability of new scientific tools and disciplines. It is in the nation’s best interests -- for good health, for a robust economy, and for scientific leadership -- to advocate for strong federal support of biomedical science in America’s great research universities. Translation of this science yields enormous benefits to our nation’s health and to the economy

HIV-1 Enhancing Effect of Prostatic Acid Phosphatase Peptides Is Reduced in Human Seminal Plasma

We recently reported that HIV-1 infection can be inhibited by innate antimicrobial components of human seminal plasma (SP). Conversely, naturally occurring peptidic fragments from the SP-derived prostatic acid phosphatase (PAP) have been reported to form amyloid fibrils called “SEVI” and enhance HIV-1 infection in vitro. In order to understand the biological consequence of this proviral effect, we extended these studies in the presence of human SP. PAP-derived peptides were agitated to form SEVI and incubated in the presence or absence of SP. While PAP-derived peptides and SEVI alone were proviral, the presence of 1% SP ablated their proviral activity in several different anti-HIV-1 assays. The anti-HIV-1 activity of SP was concentration dependent and was reduced following filtration. Supraphysiological concentrations of PAP peptides and SEVI incubated with diluted SP were degraded within hours, with SP exhibiting proteolytic activity at dilutions as high as 1∶200. Sub-physiological concentrations of two prominent proteases of SP, prostate-specific antigen (PSA) and matriptase, could degrade physiological and supraphysiological concentrations of PAP peptides and SEVI. While human SP is a complex biological fluid, containing both antiviral and proviral factors, our results suggest that PAP peptides and SEVI may be subject to naturally occurring proteolytic components capable of reducing their proviral activity

In Vivo CD8+ T-Cell Suppression of SIV Viremia Is Not Mediated by CTL Clearance of Productively Infected Cells

The CD8+ T-cell is a key mediator of antiviral immunity, potentially contributing to control of pathogenic lentiviral infection through both innate and adaptive mechanisms. We studied viral dynamics during antiretroviral treatment of simian immunodeficiency virus (SIV) infected rhesus macaques following CD8+ T-cell depletion to test the importance of adaptive cytotoxic effects in clearance of cells productively infected with SIV. As previously described, plasma viral load (VL) increased following CD8+ T-cell depletion and was proportional to the magnitude of CD8+ T-cell depletion in the GALT, confirming a direct relationship between CD8+ T-cell loss and viral replication. Surprisingly, first phase plasma virus decay following administration of antiretroviral drugs was not slower in CD8+ T-cell depleted animals compared with controls indicating that the short lifespan of the average productively infected cell is not a reflection of cytotoxic T-lymphocyte (CTL) killing. Our findings support a dominant role for non-cytotoxic effects of CD8+ T-cells on control of pathogenic lentiviral infection and suggest that cytotoxic effects, if present, are limited to early, pre-productive stages of the viral life cycle. These observations have important implications for future strategies to augment immune control of HIV