Critical role of NKT cells in posttransplant alloantibody production

We previously reported that posttransplant alloantibody production in CD8-deficient hosts is IL-4+ CD4+ T cell-dependent and IgG1 isotype-dominant. The current studies investigated the hypothesis that IL-4-producing natural killer T cells (NKT cells) contribute to maximal alloantibody production. To investigate this, alloantibody levels were examined in CD8-deficient WT, CD1d KO and Jα18 KO transplant recipients. We found that the magnitude of IgG1 alloantibody production was critically dependent on the presence of type I NKT cells, which are activated by day 1 posttransplant. Unexpectedly, type I NKT cell contribution to enhanced IgG1 alloantibody levels was interferon-γ-dependent and IL-4-independent. Cognate interactions between type I NKT and B cells alone do not stimulate alloantibody production. Instead, NKT cells appear to enhance maturation of IL-4+ CD4+ T cells. To our knowledge, this is the first report to substantiate a critical role for type I NKT cells in enhancing in vivo antibody production in response to endogenous antigenic stimuli

Racial differences in renal allograft survival: The role of systemic hypertension

Racial differences in renal allograft survival: The role of systemic hypertension. The rate of decline in the number of functioning renal allografts beyond the first year after transplantation has changed little in the last 25 years, and during long-term follow-up most allografts are lost due to chronic transplant rejection or patient death. The recipient race correlates with allograft survival, and African American recipients have a lower allograft survival than Caucasians. The goal of the present study was to identify clinical variables present during the first six months after transplantation that predict the loss of renal allografts beyond six months after transplantation, and in particular to determine the role of systemic hypertension on renal allograft survival in black and white recipients. This study includes 547 recipients of first cadaveric renal allografts performed at The Ohio State University. All patients were treated with a uniform immunosuppressive protocol and had a follow-up of at least three years. By multivariate analysis the following variables correlate with poor allograft survival: an elevated serum creatinine concentration measured six months after transplantation (SCr6mo) (P < 0.0001); black race (P < 0.0001); increasing numbers of acute rejection episodes (ATR) (P = 0.002); and young recipients (P = 0.026). Allograft survival is significantly worse in black (mean allograft half-life of 7.7 ± 1.3 years) than in white recipients (24 ± 3 years) (P < 0.0001). Black recipients also have a significantly higher six month average mean arterial blood pressure (MAP) (105 ± 8 mm Hg) than white recipients (102 ± 7 mm Hg) (P = 0.002). However, the prevalence of hypertension is not significantly different in black (33%) than in white recipients (26%). Furthermore, increasing MAP levels correlate with a shorter allograft half-life in black recipients (P = 0.0002), but not in white recipients (P = 0.84). Allograft survival was eight times shorter in hypertensive black (3.1 ± 0.7 years) than in hypertensive white recipients (24.6 ± 7 years). In contrast, allograft survival was not statistically different between normotensive black and white patients. In conclusion, the presence of poorly controlled systemic hypertension, early after renal transplantation, correlates with poor allograft survival in black recipients. Thus, systemic hypertension may explain, in part, differences in renal allograft survival between black and white patients

The effect of cross-linking of chitosan microspheres with genipin on protein release

Genipin, a natural and non-toxic cross-linking reagent, was evaluated for its effects on the drug/protein release and swelling of chitosan microspheres. Chitosan microspheres, using albumin as a model protein, were prepared and cross-linked with 0.5 mM genipin for 4 to 16 h or for 4 h using 0.5 to 2.0 mM genipin. The degree of cross-linking, swelling and the release of albumin from the microspheres was determined by the ninhydrin assay, measuring change in mass between dry and wet spheres, and in 31-day elution tests, respectively. The degree of cross-linking increased up to maximum of 33% to 34% with up to 8 hour cross-linking time or with up to 1.0 mM genipin concentration. Additional cross-linking time or concentration did not significantly increase degree of cross-linking. Swelling ratios decreased significantly from 119.2% in the uncross-linked condition to 108.8% at 16 h cross-linking time. However, increasing the genipin concentration resulted in much smaller decreases in swelling. The release of albumin was reduced with as little as 4 h cross-linking time to 30.9% of uncross-linked microspheres for up to 24 days and by as much as 52.3-60.0% for up to 31 days with 8-16 h cross-linking time. Using genipin concentrations of 1.0 to 2.0 mM for 4 h, greatly reduced albumin release to only 12.4% to 27.1% on day 24. These data demonstrate that protein and drug delivery rates from chitosan microspheres may be controlled and extended by controlling the degree of cross-linking with genipin. © 2006 Elsevier Ltd. All rights reserved

Replacement of liver parenchyma in analbuminemic rats with allogenic hepatocytes is facilitated by intrabone marrow-bone marrow transplantation

PublisherAlthough hepatocyte transplantation (HCTx) is expected to become a useful therapy for human liver diseases, allogenic hepatocytes still tend to be rejected within a short period due to host immunosurveillance. In the present study, we investigated the effect of prior bone marrow transplantation (BMTx) for the engraftment of allogenic hepatocytes using the analbuminemic rat transplantation model. The hepatocytes of Lewis (LEW) rats were not accepted in the liver of retrorsine (RS)/partial hepatectomy (PH)-treated analbuminemic F344 (F344-alb) rats, which express the disparate major histocompatibility complex (MHC) against that of LEW rats. Prior BMTx with the LEW bone marrow cells (BMCs) after sublethal irradiation achieved acceptance and repopulation of LEW hepatocytes in the liver of the RS/PH-treated F344-alb rats, associated with elevation of serum albumin. The replacement of hepatic parenchyma with albumin positive (Alb+) donor hepatocytes and elevation of serum albumin levels were dependent on the bone marrow reconstitution by donor BMCs, which was more efficiently achieved by intrabone marrow (IBM)-BMTx than by intravenous (IV)-BMTx. Our results demonstrate that efficient bone marrow reconstitution by IBM-BMTx enables the replacement of the hepatic parenchyma with allogenic hepatocytes in RS/PH-treated analbuminemic rats without immunosuppressants