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Biomedical subjects

W H Barber

Publications and source records attributed to W H Barber.

At least 19 recordsLinked to original sources
PubMed1995

Tumor necrosis factor alpha gene expression in human peritoneal macrophages is suppressed by extra-abdominal trauma.

BACKGROUND: Trauma is believed to activate immunocytes but paradoxically also increases the risk of intraperitoneal infection. OBJECTIVE: To investigate these events by evaluating changes in the cytokine control networks of human peritoneal macrophages (PM phi) early after trauma. DESIGN: Case-control study comparing cytokine messenger RNA (mRNA) expression by PM phi from patients with extra-abdominal trauma with that of both peripheral blood mononuclear cells (PBM) and PM phi obtained from healthy individuals. SETTING: Level I trauma center and basic science laboratory in a university hospital center. PATIENTS: Six patients with polytrauma (Injury Severity Score, > or = 15) with clinically negative diagnostic peritoneal lavages performed on routine indications at admission to the emergency department and six healthy age- and sex-matched individuals undergoing inguinal herniorrhaphy under local anesthesia. INTERVENTIONS: Peritoneal macrophages were isolated from diagnostic peritoneal lavages in trauma patients. Identical lavages were performed through the hernia sac in the control group. MEASUREMENTS: Cellular RNA was assayed for tumor necrosis factor alpha (TNF-alpha), interleukin-1 beta, IL-6, and IL-10 message by semiquantitative reverse-transcription polymerase chain reaction. RESULTS: Normal PM phi expressed high levels of TNF-alpha mRNA relative to PBM, but expression of the other proinflammatory cytokines was equivalent to that of PBM. Peritoneal macrophage expression of TNF-alpha mRNA was markedly (64-fold) decreased after trauma (P < .001), when PBM expression of IL-10 mRNA was increased (P = .03). CONCLUSIONS: Human PM phi constitutively show high levels of TNF-alpha message expression, and this is down-regulated by polytrauma. This might constitute a functionally "primed" state. If so, TNF-alpha down-regulation might contribute to functional PM phi suppression after systemic injury.

Adult↗
PubMed1995

Donor specific bone marrow cells suppress lymphocyte reactivity to donor antigens and differentially modulate TH1 and TH2 cytokine gene expression in the responder cell population.

Previous studies have shown that post-transplantation infusion of donor specific bone marrow following a non-specific potent immunosuppressive agent such as antilymphocyte globulin (ALG) can significantly enhance graft survival compared to ALG alone. This enhancement remains variable and is thought to occur through the induction of specific partial tolerance to the renal allograft, but the underlying cellular mechanisms have not been clearly identified. In order to improve the efficacy of this specific immunosuppressive treatment and to study the events leading to enhanced allograft survival, we sought to establish a simple in vitro model based on a mixed lymphocyte reaction (MLR). We show that cellular proliferation seen in a normal MLR can be suppressed by addition of donor specific bone marrow cells (BMC). Significantly, this suppression is not observed with either third party BMC or donor specific peripheral blood mononuclear cells (PBMC). We have defined the optimum conditions of bone marrow infusion regarding number of BMC, their handling and culture, and simple enrichment procedures. Using a semiquantitative polymerase chain reaction assay, we have studied the cytokine gene expression in MLR modulated by donor specific BMC. In an unmodified allogeneic response, the responder cells show increased expression of interleukin-2 (IL-2) gamma-interferon IFN-gamma and receptor (IL-2R) mRNA, and no IL-10 mRNA. When responder cells are cultured with BMC of the stimulator, there is a 256-fold decrease in IL-2 mRNA, and a 64-fold decrease in IFN-gamma and IL-2R mRNA. There is also a 64-fold increase in IL-10 mRNA. This effect is even more marked when the BMC are depleted of CD3+ cells. The kinetics of addition of donor specific BMC to the normal allogeneic MLR culture and specificity of the action of BMC are also elucidated. Our data suggest that the enhancement of graft survival observed with donor BMC may operate through decreased proliferation of reactive T cell clones (due to decreased IL-2/IL-2R) and suppressed monocyte functions (due to decreased IFN-gamma and increased IL-10 gene expression).

Bone Marrow↗
PubMed1992

Benefits of quadruple immunosuppressive therapy in recipients of living related donor kidneys. A review of 855 operations.

Eight hundred fifty-five living related donor transplant recipients were analyzed according to 15 potential risk factors with regard to patient and graft survival according to immunosuppression. Group I, 1968 to 1983, (n = 440 patients) received azathioprine and prednisone; group II, 1984 to 1987, (n = 229 patients) received triple therapy--azathioprine, prednisone, and cyclosporine; and group III, 1988-1991, (n = 186 patients), quadruple therapy--azathioprine, prednisone, cyclosporine, and Minnesota antilymphocyte globulin. Three important risk factors included immunosuppression, tissue typing, and race. Groups II and III had improved allograft survival over group I (p = 0.03). Patients with two haplotype matches had similar survival in all three groups. Kidney survival in one-haplotype-matched recipients improved in group II and was equal to that of the two-haplotype-matched patients in group III. Cyclosporine improved allograft survival in both races when combined with azathioprine and prednisone. Quadruple therapy improved early survival in one-haplotype black patients, even though long-term results remained better in whites. Cyclosporine did not improve graft survival in two-haplotype recipients. The addition of cyclosporine and quadruple therapy did not increase morbidity and mortality rates.

Adolescent↗
PubMed1992

Improved survival of primary cadaveric renal allografts in blacks with quadruple immunosuppression.

Black recipients of cadaveric kidneys have been shown to have a lower rate of allograft survival than whites. Data were reviewed from 642 primary cadaveric transplants: results in 276 patients (163 white and 113 black) (group 1) who had received triple therapy (azathioprine-CsA-prednisone, 1985-87) were compared with those in 366 patients (180 white and 186 black) (group 2) receiving quadruple immunosuppression (MALG-azathioprine-CsA-prednisone, 1987-90). Blacks in group 2 had better patient (97% vs. 91%, P = 0.03) and graft (77% vs. 55%, P = 0.0002) survival at 1 year than in group 1. There was no difference in these parameters among whites in either group. Racial differences in graft survival noted in group 1 disappeared in group 2. While HLA BDR matching improved in group 2 patients (P = 0.0001), whites received better matched kidneys than blacks in both groups (P = 0.001). HLA matching was associated with improved graft survival only in white recipients of 4 BDR-matched kidneys. In group 1, more blacks than whites had at least one episode of acute rejection (76% vs. 57%, P = 0.001); blacks also lost more grafts to acute and chronic rejection. In group 2, there were no racial differences in the number of rejection episodes or immunologic graft losses. Of 14 potential variables examined by parametric analysis, only quadruple therapy significantly reduced risk of graft loss in blacks. Quadruple immunosuppression improved primary cadaveric renal allograft survival in black recipients, abrogating previously noted racial differences.

Adult↗
PubMed1992

The impact of the UNOS mandatory sharing policy on recipients of the black and white races--experience at a single renal transplant center.

The impact of the United Network for Organ Sharing mandatory sharing policy on a large transplant center procuring kidneys primarily from caucasians while serving a pool of prospective recipients composed mainly of blacks is described. This policy requires that all 6-antigen-matched and phenotypically identical donor kidneys be shipped to the appropriately matched recipients. The study consisted of 49 kidneys from 25 cadaveric donors; one kidney was unusable. In general, the 33 recipients of the mandatorily shared kidneys were caucasian (94%), unsensitized (70%), and first-time transplants (73%). Allograft survival for the 24 first-time recipients was 100% (mean graft survival = 11.3 months). Of the 9 regraft kidneys, 2 have failed (mean graft survival = 11.9 months) due to chronic rejection. In comparison, the 16 paired kidneys transplanted into non-6-antigen-matched recipients exhibited a 1-year graft survival of 80% versus 92% for the 33 recipients of mandatorily shared kidneys (P = 0.01). These 16 recipients were composed of more blacks (38%), fewer regrafts (6%), and most were unsensitized (75%). All 25 cadaveric donors were caucasians with very common HLA types. Thus, kidneys provided by the UNOS mandatory sharing policy had excellent allograft survival, and the recipients were largely unsensitized caucasians receiving their first kidney. The low number of blacks receiving allografts under this policy may be due to two factors. First, the histocompatibility differences between black recipients and the primarily caucasian cadaveric donor pool limit the number of kidneys available to blacks. Secondly, blacks do not have access to the best-matched kidneys, in part due to few black donors, their best source for well-matched kidneys. Thus, the mandatory sharing program is of clear benefit to the recipients of these well-matched kidneys; however, for a local program servicing a waiting list composed of 64% blacks the policy has been of limited value. In contrast, over 50% of local cadaveric transplants are into black recipients in a waiting time of 197 days, one third the national average for blacks. In conclusion, this study supports efforts to improve graft survival through matching but emphasizes the need to broaden our efforts in all areas of research and organ procurement to serve the entire recipient population, regardless of race.

Black People↗
PubMed1991

OKT3 first-dose reaction: association with T cell subsets and cytokine release.

Use of the monoclonal antibody OKT3 to prevent or treat allograft rejection has become commonplace. Its administration is often complicated by serious side effects, usually occurring within one to two hours after OKT3 is given, and is termed first-dose reaction. The mechanism underlying these signs and symptoms is poorly defined, but may be related to cytokine release. Twenty-three kidney or kidney/pancreas transplant recipients received OKT3 as treatment of acute rejection. Signs and symptoms occurring after the first dose were observed and quantitated prospectively, and a reaction score was calculated. Blood was drawn immediately before, and at 2 and 24 hours after the first dose of OKT3 for determination of interleukin-2 (IL2), interferon-gamma (IFN gamma), and tumor necrosis factor-alpha (TNF alpha) levels, and flow cytometric analysis of T cell subsets. Two groups were defined based on severity of first-dose reaction. Group 1 patients (N = 11) had very mild reactions (reaction score less than or equal to 3); Group 2 patients (N = 12) had more severe reactions (score greater than or equal to 5). All patients demonstrated a significant rise in serum TNF alpha from baseline to two hours after OKT3 (9 +/- 3 pg/ml to 378 +/- 54 pg/ml, P less than 0.0001), and there was significant correlation between reaction scores and two-hour TNF alpha levels (P = 0.005). Group 2 patients had higher TNF alpha levels at two hours than did Group 1 patients (484 +/- 75 pg/ml vs. 263 +/- 62 pg/ml, P = 0.04). Levels of IL2 and IFN gamma were not elevated at any sampling time.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Long-term results of a controlled prospective study with transfusion of donor-specific bone marrow in 57 cadaveric renal allograft recipients.

Experimental studies have shown that antilymphocyte globulin combined with transfusion of donor-specific bone marrow cells can induce partial tolerance to allograft tissue. We have adapted these protocols to clinical use and present the results of 57 cadaveric renal allograft recipients who received Minnesota ALG followed by the transfusion of cryopreserved donor-specific bone marrow. A group of 54 patients received the contralateral kidney and similar immunosuppression without the marrow transfusion and serve as controls. Both groups received quadruple immunosuppression with MALG, cyclosporin, azathioprine, and prednisone. In the bone marrow group, after a 10-14 day induction course of ALG, cryopreserved marrow was transfused on the seventh day after the last dose of ALG. The median follow-up in both groups is 16 months, (range 2.5-33 months). Six grafts have been lost in the bone marrow group, (three rejections, 2 deaths [Cr 2.0, 2.3], 1 recurrent disease). In the control group 16 grafts have been lost (13 rejections, 3 deaths [Cr 1.7, 2.5, 3.0]). Five patients in the control group have biopsy-proved chronic rejection compared to one in the bone marrow group. 17 patients in the bone marrow group have been tapered off the prednisone, and three of these patients have had mild late rejection episodes without graft loss. The two groups were compared for differences in the number of rejection episodes, estimated renal plasma flow, glomerular filtration rate, and urine protein. No differences were found. The allograft survival of the bone marrow group was significantly greater (P less than .01) than the control group. The graft survival rates for the bone marrow group at 12 and 18 months were 90% (confidence limits [CL] 85-94) and 85% (CL 78-90), respectively. In the the control group the 12 and 18 month allograft survival rates were 71% (CL 63-78) and 67% (CL 58-74), respectively. The survival in the control group was similar to our overall transplant experience with quadruple therapy. Mixed lymphocyte culture analysis shows a trend to diminished donor-specific responsiveness in the bone marrow group. The use of cryopreserved donor-specific bone marrow is associated with improved allograft survival in cadaveric kidney allograft recipients. However, a more effective induction protocol is needed to reduce the overall number of rejection episodes.

Antilymphocyte Serum↗
PubMed1991

Analysis of 22 years experience in living-related transplantation at the University of Alabama in Birmingham.

Over the 22 years comprising this review of living-related renal allografts, 3 distinct eras of immunosuppression protocols were used; Era I-aziathioprine and prednisone, Era II-cyclosporine, azathioprine, and prednisone; and Era III-Minnesota antilymphocyte globulin, cyclosporine, azathioprine, and prednisone. We analyzed both recipient and donor populations for graft and patient survival related to race, haplotype matching, diabetes, and immunosuppressive agents. Graft and patient survival have remained unchanged in 2-haplotype-matched recipients throughout the differing immunosuppression eras. The addition of cyclosporine, however, improved graft survival in the 1-haplotype living-related recipient. During the cyclosporine era, 1-haplotype White living-related recipient graft survival was significantly greater than 1-haplotype Black living-related recipient survivals. The reason for this disparity in graft survival does not appear to be related to noncompliance. The parametric hazard function analysis of the constant phase did not identify cyclosporine as a risk factor for late graft loss, suggesting that long-term cyclosporine usage may decrease the risk of graft loss. However, diabetes was demonstrated to be a risk factor for late graft loss. In diabetics, late graft loss is most likely secondary to death (usually cardiovascular) with a functioning graft. The organ donor pool is being expanded through the utilization of both older donors and living-unrelated donors. Graft survival in the living-unrelated group has been comparable to that of 1- and 2-haplotype-matched recipients. Results with older donors reveal donor age as a risk factor for late graft loss. The issue of living-unrelated transplantation remains controversial. In over 20 years of follow-up on our living-related donor population, we were unable to demonstrate any adverse long-term effects on renal function. Results of our analysis indicate that living-related renal donation continues to be a safe and valuable avenue for kidney transplantation.

Adolescent↗
PubMed1990

Cyclosporine-induced changes in glomerular filtration rate and urea excretion.

PURPOSE: Cyclosporine is the mainstay of many immunosuppressant protocols, but confers a significant risk of nephrotoxicity. We sought to clarify the effects of cyclosporine on renal function in renal transplant recipients after induction of mild intravascular volume depletion. PATIENTS AND METHODS: Two groups of renal transplant patients with normal allograft function at least 6 months after transplantation whose immunosuppressive regimens differed only by the presence or absence of cyclosporine usage were enrolled in a 10-day in-hospital protocol. After a 3-day control period, intravascular volume depletion was produced by dietary restriction of sodium chloride for 4 days and the administration of furosemide. Creatinine and urea clearances, true glomerular filtration rate (GFR) (by radioisotope technique), and the fractional excretion of sodium were measured. The patients were subsequently given a high amount of sodium chloride by intravenous infusion (3.8 mEq/kg body weight/day) for 3 days and the studies were repeated. RESULTS: Ten patients treated with azathioprine and prednisone (azathioprine-treated) and nine patients treated with cyclosporine, azathioprine, and prednisone (cyclosporine-treated) were enrolled. The two groups developed a similar degree of intravascular volume depletion; blood pressure did not change and urine flow rates did not differ between the groups throughout the protocol. The cyclosporine-treated patients showed significant decreases in GFR, creatinine clearance, and urea clearance, and increases in blood urea nitrogen (BUN) and percent urea reabsorption after intravascular volume depletion; these findings resolved after challenge with the sodium chloride load. In contrast, the azathioprine-treated patients' BUN, urea clearance, GFR, and creatinine clearance did not significantly change throughout the protocol. The decrease in the fractional excretion of sodium after intravascular volume depletion was significantly greater in the cyclosporine-treated patients. CONCLUSION: Cyclosporine predisposes to acute reversible nephrotoxicity by compromising the renal compensatory mechanisms. Proximal tubular function, as manifested by urea and sodium reabsorption, remains intact.

Adult↗
PubMed1990

Donor antigen-specific immunosuppression in cadaveric and living-related donor kidney allograft recipients.

This is a review of the University of Alabama Hospital's clinical experience with 1-haplotype-mismatched LRD renal transplants, utilizing a stored-blood DST protocol and with cadaveric renal transplants utilizing DBM transfusion. Stored-blood DST does not significantly improve LRD allograft survival either in Aza-, P-, or CsA-treated patients, although there is a trend toward better survival in Aza/DST versus Aza/no-DST recipients (78% vs 84% 12-month allograft function). Importantly, although the early acute phase graft loss was slightly diminished by DST, the late phase loss (slope of curve) was essentially identical to nontransfused patients. Thus, we cannot demonstrate a beneficial effect by the use of DST in achieving improved long-term graft survival in recipients of 1-haplotype-matched recipients. The use of cryopreserved DBM transfusions in cadaveric allograft recipients, however, has resulted in significantly improved survival compared to control patients who received the marrow donor's contralateral kidney and similar immunosuppression without marrow infusion [92% vs 73% (p = 0.01)]. DBM-transfused patients demonstrate diminished donor-specific responsiveness in MLC compared with controls. P withdrawal can be accomplished safely in the majority of marrow recipients; however, this has not been tested in the controls. Donor-nucleated cells persist in the peripheral blood of some DBM-transfused patients for at least 2 years following transplantation. Presently, the significance of persistent chimerism in these patients with respect to donor responsiveness and allograft tolerance is unclear.

Azathioprine↗
PubMed1989

Use of cryopreserved donor bone marrow in cadaver kidney allograft recipients.

Donor-specific unresponsiveness to organ allografts remains an elusive goal in clinical transplantation, as most successful experimental protocols for the production of antigen-specific immunosuppression require lengthy recipient pretreatment. The use of an induction course of antilymphocyte serum (ALS) beginning at the time of transplantation, followed by the transfusion to the recipient of donor-specific bone marrow, has been shown in animals to induce prolonged allograft survival and is applicable for use in cadaver donor clinical transplantation. Our preliminary data in humans suggest that the transfusion of cryopreserved cadaver donor bone marrow following a short course of ALS is safe and does not induce graft-versus-host disease or allograft rejection. Twenty patients have been included in the protocol and 19 have been discharged from the hospital with functioning kidney transplants. One graft failed at 3 months. Eight patients have been withdrawn entirely from prednisone immunosuppression 3-6 months following transplantation. The contralateral kidneys from the marrow donors were transplanted into an additional 20 patients who received sequential immunosuppressive therapy without marrow transfusion. Three of these grafts have failed within 3 months due to acute rejection. Donor marrow transfusion may give rise to improved allograft and patient survival in clinical transplantation while at the same time allow for reduced requirements for nonspecific immunosuppressive agents with their undesirable side effects.

Bone Marrow Transplantation↗
PubMed1989

Successful renal allografts in recipients with crossmatch-positive, dithioerythritol-treated negative sera. Race, transplant history, and HLA-DR1 phenotype.

Graft survival was examined in 15 renal allograft recipients from a group of 20 patients with IgM autolymphocytotoxic antibody that could be removed in a crossmatch assay using a reducing agent, dithioerythritol (DTE). The significant differences in this group of 20 patients compared with end-stage renal disease (ESRD) patients lacking autolymphocytotoxic antibodies included an increased frequency of black patients (P = 0.002), a lack of previous transplants (P = 0.003), and an increased frequency of the HLA-DR1 phenotype (P = 0.0001). Sex and the number of transfusions did not appear significant, whereas the cause of ESRD was primarily systemic lupus erythematosus. Fifteen of the 20 patients were transplanted against a positive donor crossmatch. Eleven were recipients of cadaveric kidneys, nine of which are still functioning for periods ranging from 0.5 to 40 months. Two fo the cadaveric recipients died with functional grafts. Four received living-related donor transplants, one of which was lost to acute rejection one month posttransplant, while the remaining three have survived 1.5, 9, and 21 months, respectively. Fourteen patients had immediate allograft function with no hyperacute rejection and only one case of acute tubular necrosis (ATN) was found. In summary, a negative crossmatch using DTE-treated, autologous reactive recipient sera may identify a group of patients who can be transplanted with minimal concern for hyperacute rejection or ATN. In addition to cause of ESRD, race, transplant history, and HLA-DR phenotype may further define this group of transplant candidates having IgM autolymphocytotoxic antibody. Extrapolation of these conclusions to transplant candidates lacking autolymphocytotoxic antibodies is not warranted.

Absorption↗