Biomedical subjects

G L Bumgardner

Publications and source records attributed to G L Bumgardner.

At least 19 recordsLinked to original sources

PubMed2006

Activation and maturation of alloreactive CD4-independent, CD8 cytolytic T cells.

The goal of this study was to determine the in vivo conditions that promote activation of the (CD4-independent) CD8+ T cell-mediated rejection pathway. We have previously noted that hepatocellular but not islet allografts readily activate this rejection pathway. In the current study, we utilized these two cell transplant models to investigate whether differences in host cell recruitment to the graft site, expression of T-cell activation markers by CD8+ graft infiltrating cells (GICs), and/or development of delayed-type hypersensitivity (DTH) and cytotoxic T lymphocyte cell-mediated effector functions could account for the differential transplant outcomes. The collective results demonstrate that recruitment of CD8+ T cells to the site of transplant, CD103 or CD69 expression on CD8+ GICs, and activation of alloreactive DTH responses are insufficient to initiate CD4-independent, CD8-dependent transplant rejection. Instead, rejection by alloreactive (CD4-independent) CD8+ T cells correlated with expression of CD25, CD154 and CD43 by CD8+ GICs, in vitro alloproliferation by recipient CD8+ T cells, and the development of in vivo allospecific cytolytic effector function. These results suggest that tissue-derived factors influence the activation and maturation of (CD4-independent) CD8+ T cells into cytolytic effectors, which correlates with transplant rejection.

Animals↗

PubMed2001

Results of 3-year phase III clinical trials with daclizumab prophylaxis for prevention of acute rejection after renal transplantation.

BACKGROUND: Daclizumab (Zenapax, Roche Pharmaceuticals), a humanized monoclonal antibody directed against the alpha chain of the interleukin 2 receptor, has been shown to reduce the incidence of acute rejection at 6 months after renal transplantation in two phase III clinical trials. This report presents the combined 1- and 3-year outcomes of kidney transplant recipients who participated in these two phase III clinical trials. METHODS: Data from two multicenter, randomized, placebo-controlled trials were evaluated with regard to graft survival, patient survival, incidence of malignancies (including lymphoma), renal function (serum creatinine and glomerular filtration rate [GFR]), and current maintenance immunosuppressive regimen. In addition, the impact of acute rejection and acute rejection requiring treatment with antilymphocyte therapy upon 3-year graft survival was evaluated. Daclizumab was compared to placebo on a background of cyclosporine (CsA), azathioprine, and corticosteroids (triple therapy, TT) or CsA and corticosteroids (double therapy, DT). RESULTS: Treatment with daclizumab in the pooled analysis demonstrated a significant reduction in the incidence of biopsy-proven acute rejection episodes at 12 months posttransplant (43% vs. 28%, P<0.001). The 3-year graft survival was not significantly different between placebo and daclizumab-treated patients in the TT trial (83% vs. 84%) or in the DT trial (78% vs. 82%). Pooled patient survival was excellent in both placebo- (91%) and daclizumab- (93%) treated patients. The incidence of malignancies or posttransplant lymphoproliferative disorder (PTLD) in placebo- versus daclizumab-treated groups was comparable in both clinical trials. Renal function was similar between placebo- and daclizumab-treated groups in both the TT and DT trials. The occurrence of delayed graft function, acute rejection requiring antilymphocyte therapy at 6 months, and acute rejection at 12 months posttransplant were associated with decreased graft survival rates at 3 years posttransplant. CONCLUSIONS: The beneficial effect of daclizumab prophylaxis upon the incidence of acute rejection after renal transplant with TT or with DT was not associated with adverse clinical sequelae, including the development of PTLD, at 3 years posttransplant. There was no beneficial effect of daclizumab on graft survival at 3 years, but the trial was inadequately powered to detect this. Both studies showed excellent graft and patient survival at 3 years.

Acute Disease↗

PubMed2001

Daclizumab (humanized anti-IL2Ralpha mAb) prophylaxis for prevention of acute rejection in renal transplant recipients with delayed graft function.

BACKGROUND: The purpose of this retrospective study was to determine the benefits of daclizumab, (Zenapax, Roche Pharmaceuticals) a humanized anti-interleukin-2Ralpha (IL-2Ralpha) monoclonal antibody, for prevention of acute rejection in renal transplant recipients with delayed graft function (DGF). METHODS: Data from two multicenter randomized placebo-controlled trials were pooled. DGF was defined by urine output <30 cc/hour, decline in serum creatinine of <0.5 mg/dl, or the need for dialysis within the first 24 hours after transplantation. RESULTS: At one year posttransplantation, the incidence of biopsy-proven acute rejection in patients with DGF was reduced from 44% in the placebo group to 28% in the daclizumab group. (P=0.03) Prophylaxis with daclizumab also delayed the onset of the first biopsy-proven acute rejection episode in patients with DGF from 29+/-43 days in the placebo group to 73+/-70 days in the daclizumab group. (P=0.004) The graft survival rates in patients with DGF at 1 year posttransplantation were 78% in the placebo group and 82% in the daclizumab treated group. (P=ns) Three patients in the placebo-treated group with DGF experienced graft loss due to acute rejection, whereas no patients in the daclizumab-treated group with DGF had graft loss due to acute rejection. The 1-year patient survival rate in those with DGF in the placebo and daclizumab groups were 93% and 98%, respectively. (P=ns) CONCLUSIONS: Daclizumab effectively reduced the incidence and delayed the onset of biopsy-proven acute rejection in this high-risk subgroup of patients with DGF after renal transplantation. Graft and patient survival rates were similar between placebo- and daclizumab-treated patients with DGF.

Acute Disease↗

PubMed2001

A randomized prospective trial of OKT3 induction in the current immunosuppression era.

Recent improvements in immunosuppression and subsequent decreases in the incidence of acute rejection have brought into question the benefit of the use peri-transplant antibody therapy (i.e. induction therapy). In the current era of immunosuppression that includes mycophenolate mofetil (MMF) and cyclosporine emulsion (Neoral, Novartis, Basle, Switzerland), we designed and have completed a prospective, randomized trial to address this question. Cadaveric and living donor renal allograft recipients were randomized to receive either OKT3/MMF/delayed Neoral/prednisone or MMF/immediate Neoral/prednisone without OKT3. The incidence of rejection episodes was the primary end point. Patients with delayed graft function were excluded. All rejection episodes were biopsy proven and all patients have been followed for a minimum of 2 yr. Fifty-four patients received OKT3 induction, of which 6 patients suffered a rejection episode (11%), while 13 patients (27%) not receiving OKT3 (p=0.04) had a rejection episode. Four patients in the no OKT3 group suffered multiple rejections, while there were only 2 with more than one episode in the OKT3 group. There was no increased incidence of infectious complications in the group receiving OKT3. Hospital costs tended to be higher in the OKT3-treated group, but were not significantly different. The low incidence of rejection in the OKT3-treated group was intriguing and validates the use of antibody therapy in the early post-operative periods even in the era of improved baseline immunosuppression.

Adolescent↗

PubMed2000

Rejection responses to allogeneic hepatocytes by reconstituted SCID mice, CD4, KO, and CD8 KO mice.

INTRODUCTION: The purpose of the current study was to investigate the capacity of CD4+, CD8+, or non-T cells to independently initiate acute rejection of allogeneic hepatocytes using reconstituted SCID, CD4 or CD8 knockout (KO) recipient mice. METHODS: Allogeneic hepatocytes (FVB/N, H-2q) were transplanted into C57BL/6.SCID (H-2b), CD4 KO (H-2b), CD8 KO (H-2b), or beige/beige (H-2b) mice. SCID mice with functioning hepatocellular allografts subsequently received purified non-T cells (NTC), CD4+, or CD8+ splenocytes. Some mice were treated with anti-CD4, anti-CD8, and/or anti-nkl.1 mAb. Recipient mice were also assessed for donor-reactive delayed-type hypersensitivity (DTH) responses and donor-reactive alloantibody production. RESULTS: Median hepatocellular allograft survival time (MST) was 28 days in CD4+ reconstituted SCID mice and 14 days in CD8+ reconstituted SCID mice. SCID hosts reconstituted with NTC demonstrated indefinite hepatocellular allograft survival (>120 days). MST was 10 days in untreated beige/beige (NK cell deficient) mice. MST was 14 days in untreated, 35 days in anti-CD4 mAb treated, and 10 days in anti-nkl.1 mAb treated CD8 KO mice. MST was 10 days in untreated, 35 days in anti-CD8 mAb treated, and 7 days in anti-nk1.1 mAb treated CD4 KO mice. Donor-reactive DTH responses were not detected in reconstituted SCID mice, were minimal in CD4 KO mice, and were prominent in CD8 KO mice after rejection of allogeneic hepatocytes. Similarly, donor-reactive alloantibody, was not detected in CD4 KO hosts, but was readily detected in CD8 KO hosts. CONCLUSIONS: These studies show that both CD4+ and CD8+ T cells (but not host NTC) can independently initiate the rejection of allogeneic hepatocytes. While hepatocyte rejection by isolated CD4+ T cells is not surprising, rejection by CD8+ T cells (in the absence of CD4+ T cells) was unusual, and may explain the failure of "standard" immunosuppressive regimens to suppress acute rejection of allogeneic hepatocytes, as noted in prior studies. Furthermore, NK cells do not appear to be required for either CD4+ T cell or CD8+ T cell initiated hepatocyte rejection.

Acute Disease↗

PubMed2000

Pulmonary Rhizopus infection in a diabetic renal transplant recipient.

Infectious complications after renal transplantation remain a major cause of morbidity and mortality. Mucormycosis is a rare infection in renal transplant recipients; however, mortality is exceedingly high. Risk factors predisposing to this disease include prolonged neutropenia, diabetes, and patients who are immunosuppressed (Singh N, Gayowski T, Singh J, Yu LV. Invasive gastrointestinal zygomycosis in a liver transplant recipient: case report and review of zygomycosis in solid-organ transplant recipients, Clin Infect Dis 1995: 20: 617). Life-threatening infections can occur, as this fungus has the propensity to invade blood vessel endothelium, resulting in hematological dissemination. We report a case of cavitary Rhizopus lung infection, 2 months after renal transplantation, where the patient was treated successfully with Amphotericin B and surgical resection of the lesions with preservation of his allograft function. In this era of intensified immunosuppression, we may see an increased incidence of mucormycosis in transplant population. Invasive diagnostic work-up is mandatory in case of suspicion; Amphotericin B and, in selected cases, surgical resection are the mainstays of therapy.

Diabetic Nephropathies↗

PubMed2000

Unusual patterns of alloimmunity evoked by allogeneic liver parenchymal cells.

Despite the widely accepted view of the liver as an immunoprivileged tissue, purified allogeneic liver parenchymal cells delivered to the liver of a recipient mouse are highly antigenic. A functional transgenic model of hepatocyte transplantation in mice is used to explore host immune responses to allogeneic hepatocytes. Transplanted hepatocytes expressing human alpha-1-antitrypsin (hA1AT) are monitored for survival by the secretion of the transgene product hA1AT. Transplantation of transgenic hepatocytes into syngeneic or immunoincompetent severe combined immunodeficiency disease (SCID) mice results in indefinite hepatocellular allograft survival. However, transplantation of transgenic hepatocytes into allogeneic hosts results in rapid hepatocyte rejection. This rejection response is associated with prominent delayed type hypersensitivity responses to cellular alloantigen but minimal donor-reactive humoral immunity. Hepatocyte rejection is not controlled by host treatment with anti-CD4 mAb despite the ability of the same treatment regimen to produce indefinite survival of donor-matched heart allografts. Host immune responses to allogeneic hepatocytes utilize CD40L/CD40 but not CD28/B7 co-stimulation, unlike the activation of both of these systems in responses to other allografts. Furthermore, C57BL/6 mice which have been induced by anti-CD4 mAb or gallium nitrate treatment to accept heart allografts promptly reject donor-matched transgenic hepatocytes. Studies in reconstituted SCID, CD4 knockout (KO), and CD8 KO mice demonstrate that hepatocyte rejection can be initiated independently by either CD4+ T cells or CD8+ T cells, which again diverges from what has been observed for most other types of allografts. This may account for the relative resistance to immunoprotection for hepatocellular allografts with conventional immunosuppressive agents and to immunoregulatory states induced by other allografts. Three models of hepatocyte rejection are discussed.

Animals↗

PubMed2000

Different costimulation signals used by CD4(+) and CD8(+) cells that independently initiate rejection of allogenic hepatocytes in mice.

The current study evaluated the role of CD40/CD40 ligand (CD40L) and CD28/B7 costimulation signals during alloimmune responses independently mediated by CD4(+) or CD8(+) T cells. Allogeneic hepatocytes were transplanted into CD8 or CD4 knock out (KO) mice under cover of costimulatory blockade. Rejection of FVB/N (H-2(q)) hepatocytes occurred by day 10 posttransplant in untreated CD8 or CD4 KO (H-2(b)) mice. Treatment of CD8 or CD4 KO mice with anti-CD40L monoclonal antibody (mAb; MR1) resulted in significant prolongation of hepatocyte survival indicating that CD40/CD40L interactions were critical in both CD4(+) and CD8(+) T-cell initiated hepatocyte rejection. Anti-CD40L mAb also prolonged hepatocyte survival in B-cell KO (H-2(b)) mice, indicating that the efficacy of CD40/CD40L blockade in preventing hepatocyte rejection was B-cell (and antibody) independent. In contrast, treatment with CTLA4 fusion protein (CTLA4Ig), prolonged hepatocyte survival in CD8 KO but not CD4 KO mice, showing that CD28/B7 interactions were important in CD4(+) but not CD8(+) T-cell initiated hepatocyte rejection. Under selected circumstances, such as in CD40 KO mice, both CD4(+) and CD8(+) T cells mediate hepatocyte rejection in the absence of CD40/CD40L costimulation and without a significant contribution from CD28/B7 costimulation signals. These results highlight the disparate roles of CD40/CD40L and CD28/B7 costimulation signals in CD4(+) versus CD8(+) T-cell mediated immune responses to allogeneic hepatocytes. The CD4(+) T-cell independent, CD40L-sensitive, CD28/B7-independent pathway of CD8(+) T-cell activation in response to transplantation antigens is novel.

Abatacept↗

PubMed1999

Obese living kidney donors: short-term results and possible implications.

BACKGROUND: Living kidney donation has increased recently as the shortage of cadaveric organs continues. This increase has occurred in part, due to expanded donor criteria, including obese patients. This is a potential concern because obesity is associated with surgical complications, possibly death, and chronic medical problems. To address this concern, we examined the outcome of a large group of obese (ObD) and nonobese living kidney donors (NObD). METHODS: A total of 107 obese (body mass index> or =27 kg/m2) and 116 nonobese (body mass index<27 kg/m2) living kidney donors donating at a single institution between 1990 and 1996 were studied. Surgical complications, operative duration, and hospital length of stay were assessed. Preoperative blood pressure, serum creatinine, creatinine clearance, protein excretion, fasting glucose, and hemoglobin A1C were measured and first degree relatives with diabetes were identified. RESULTS: Overall complications were significantly more common in ObD, 16.8 vs. 3.4% (P=0.0012). The majority of complications in the entire cohort, 56%, were wound related and were significantly more common in ObD (P=0.016). There was no significant increase in nonwound-related infections, bleeding, or cardiopulmonary events. There were no deaths or major complications. Operative time was significantly longer in ObD 151+/-30 vs. 141+/-29 min (P<0.05) but hospital duration was no different. Predonation, blood pressure in ObD was significantly higher, (P<0.05) and they more often had a family history of diabetes, 46 vs. 30% (P<0.05) than nonobese donors. Renal function, proteinuria, fasting glucose, or hemoglobin A1C were no different. CONCLUSION: With prudent selection, the use of obese living kidney donors appears safe in the short term. They experience more minor complications, usually wound related, and slightly longer operations. Given a higher baseline blood pressure and family history of diabetes, the long-term effect on the remaining solitary kidney in ObD needs to be examined.

Adult↗

PubMed1999

Patterns of immune responses evoked by allogeneic hepatocytes: evidence for independent co-dominant roles for CD4+ and CD8+ T-cell responses in acute rejection.

INTRODUCTION: This is the first in a series of reports that characterizes immune responses evoked by allogeneic hepatocytes using a functional model of hepatocyte transplantation in mice. METHODS: "Donor" hepatocytes expressing the transgene human alpha-1-antitrypsin (hA1AT-FVB/N, H2q) were transplanted into C57BL/6 (H2b) or MHC II knockout (H2b) hosts treated with anti-CD4, anti-CD8, or a combination of anti-CD4 and anti-CD8 monoclonal antibodies (mAbs). Hepatocyte rejection was determined as a loss of circulating ELISA-detectable transgene product (hA1AT). In addition, some C57BL/6 mice underwent transplantation with FVB/N heterotopic cardiac allografts and were treated with anti-CD4 mAb. Cardiac allograft rejection was determined by palpation. Graft recipients were tested for donor-reactive alloantibodies and donor-reactive delayed-type hypersensitivity (DTH) responses. RESULTS: The median survival time (MST) of allogeneic hepatocytes in normal C57BL/6 mice was 10 days (no treatment), 10 days (anti-CD4 mAb), 14 days (anti-CD8 mAb), and 35 days (anti-CD4 and anti-CD8 mAbs). The MST of hepatocytes in B6 MHC class II knockout mice was 10 days (no treatment) and 21 days (anti-CD8 mAb). The MST of cardiac allografts was 11 days (no treatment) and >100 days (anti-CD4 mAb). Donor-reactive DTH responses were readily detected in both untreated and mAb-treated recipients. Donor-reactive alloantibody was barely detectable in untreated hosts. CONCLUSIONS: These studies demonstrate that allogeneic hepatocytes are highly immunogenic and stimulate strong cell-mediated immune responses by both CD4+ and CD8+ T cells, even when treated with agents that can cause acceptance of cardiac allografts. Indeed, CD4+ or CD8+ T cells seem to independently cause hepatocellular allograft rejection. Allogeneic hepatocytes evoked strong donor-reactive DTH responses but were poor stimuli for donor-reactive antibody production. This is an unusual pattern of immune reactivity in allograft recipients.

Animals↗

PubMed1999

Pathologic classification of chronic allograft nephropathy: pathogenic and prognostic implications.

BACKGROUND: After transplantation renal allografts frequently develop interstitial fibrosis and tubular atrophy, and these pathologic changes are the hallmarks of chronic allograft nephropathy (CN). However, the diagnosis of CN has no specific pathogenic implications. In this study we sought to determined whether a subclassification of CN according to vascular pathology correlates with posttransplant events, particularly acute rejection, and graft survival. METHODS: A total of 419 patients with moderate to severe CN were subdivided into: (1) transplant arteriopathy (TA, n=233, 56%); (2) arteriolar hyalinosis (AH, n=89, 21%); and (3) no characteristic vascular pathology (IFb, n=97, 23%). RESULTS: Patients with AH differed significantly from patients with TA or IFb in the following parameters: (1) AH was diagnosed later after transplantation (P=0.001); (2) fewer patients with AH had acute rejection (AR) before the diagnosis of CN (P<0.0001). For example, 44% of AH and 75% of TA had AR before CN; (3) patients with AH also had fewer AR episodes than the other two groups (P<0.0001); finally, (4) graft survival was better in patients with AH than in patients with TA (P=0.01 by chi2, P=0.001 by Cox). In contrast, there were no significant differences between patients with TA and IFb. By multivariate analysis the survival of grafts with CN correlated with: (1) serum creatinine at diagnosis (P<0.0001), (2) recipient's weight (P=0.004); (3) presence of FGS or level of proteinuria (P=0.03); and (4) the occurrence of AR after the diagnosis of CN (P<0.0001). Regarding the latter, AR were more common (P=0.007) and more numerous (P=0.005) in patients with TA or IFb than in AH. CONCLUSIONS: CN can be classified according to vascular pathology in the majority of cases, and this classification correlates with graft survival. Although some forms of CN are closely associated with the occurrence of AR others are not. This study also uncovered several variables that correlate with the survival of grafts with CN.

Adult↗

PubMed1999

Increased incidence of gastrointestinal surgical complications in renal transplant recipients with polycystic kidney disease.

BACKGROUND: We had the impression that, although our renal transplant recipients with polycystic kidney disease (PKD) had excellent long-term renal graft function, they had an increased incidence of postoperative gastrointestinal (GI) complications. METHODS: Over a 10-year period (1987 through 1996), 1467 renal transplants were performed in 1417 patients; 145 of these transplants involved PKD recipients. In the PKD group, 18 patients (12.4%) developed a posttransplant complication necessitating GI surgery (PKD-GI), an incidence twice that in the non-PKD recipients (73 patients or 6.2%, non-PKD-GI). RESULTS: PKD and non-PKD recipients displayed no significant difference in mortality. The PKD patients had better long-term renal graft survival than the non-PKD patients (P=0.08). There was no difference in mortality (P>0.6) or renal graft survival (P>0.6) between the PKD-GI and PKD-non-GI groups. The PKD-GI group had no increased mortality over the non-PKD-GI patients (P>0.6), despite a higher incidence of GI surgical complications in the PKD group versus the non-PKD group (overall: 12.4 vs. 6.2%, P<0.01; within 90 days of transplant: 7.6 vs. 3.3%, P<0.02) and a greater propensity for small and large bowel complications (overall: 9.0 vs. 2.6%; P< 0.001; less than 90 days: 6.9 vs. 2.0%, P<0.002). The PKD-GI recipients tended toward less long-term graft loss than their non-PKD-GI counterparts (11.1 vs. 27.4%; P=.22). The PKD-GI recipients suffered no acute rejection episodes within 90 days after their GI operation versus 11 of 73 non-PKD-GI recipients (O vs. 15.1%; P=0.075). CONCLUSIONS: PKD recipients of renal grafts should be watched closely early after transplant because of their increased risk of GI complications. These complications resulted in no increase in mortality or graft loss compared to non-PKD recipients with GI complications despite the PKD group's higher incidence of bowel perforation and increased age at time of transplant.

Adult↗

PubMed1999

Transplantation and cytokines.

Transplantation of foreign tissue initiates complex inflammatory responses that are mediated by cytokines and that, in the absence of immunosuppression, usually result in acute graft rejection and graft destruction. Thus, the study of cytokines in transplantation research has been pursued with great interest. Cytokine biology has evolved from an era that focused on the identification and cataloguing of newly discovered cytokines to one that addresses (1) the complexity of cytokine interactions with other cytokines, with other biologic mediators, and with the extracellular matrix; and (2) the diversity of cytokine effects upon both lymphoid and nonlymphoid cell types. This article reviews the basic principles of transplant immunology and discusses experimental data regarding the role of prototypic cytokines in allograft rejection, in general, and liver allograft rejection, in particular.

Animals↗

PubMed1998

Costimulation pathways in host immune responses to allogeneic hepatocytes.

BACKGROUND: This study investigated the role of the CD28/B7 (blocked by CTLA4Ig) and CD40/CD40L (blocked by MR1) costimulation pathways on in vivo host T-cell- mediated immune responses to allogeneic hepatocytes. METHODS: Survival of allogeneic hepatocytes (H-2q) in C57BL/6 (H-2b) mice untreated or treated with MR1, CTLA4Ig, L6 (control fusion protein), or a combination of MR1 and CTLA4Ig fusion protein was determined. RESULTS: Median survival time for hepatocellular allografts was 10, 84, 10, 10, and 84 days in untreated (n= 10), MR1-treated (n=7) (P<.0001), CTLA4Ig-treated (n=7) (P=0.02), L6-treated (n=3) (P, not significant), and the combination of MR1- and CTLA4Ig-treated (n=6) (P=0.0003) groups, respectively. CONCLUSIONS: Host treatment with MR1, but not CTLA4Ig, prolonged hepatocellular allograft survival. These data suggest that CD28/B7 interactions appear relatively unimportant, whereas CD40/CD40L interactions provide critical costimulator signals for T-cell-dependent immune responses to allogeneic hepatocytes.

Abatacept↗

PubMed1998

Clinical implications of the diagnosis of renal allograft infarction by percutaneous biopsy.

BACKGROUND: Herein we investigated the relationships between acute rejection (AR), infection, and renal allograft infarcts, particularly those infarcts that occur beyond the immediate posttransplant period and that affect functioning grafts. METHODS: Infarcts (n=59) were classified as: (1) early (EI; <2 months after transplant; n=32); or (2) late (LI; >2 months; n=27). Controls included patients with severe AR but without infarction (n=84). RESULTS: There were not significant differences in donor or recipient characteristics between infarcts and controls. At diagnosis, patients with infarcts were more likely to be infected (30%) than controls (14%, P=0.01); 15% of infarcts and 1% of controls had disseminated cytomegalovirus (P=0.04). Infarct and AR coexisted in the biopsy specimens of 66% of patients with EI and 62% of patients with LI, but the AR severity ranged from borderline to severe. Furthermore, 30% of patients with EI/LI had a history of severe AR. Graft survival was 47% in patients with EI, 22% in patients with LI (NS), and 71% in controls (P<0.0001, chi-square and Cox regression). Correlates of better graft survival in infarcts included: older recipient (P=0.03); smaller area of infarction in the biopsy specimen (P=0.04); and use of anti-AR therapy (P=0.03). Therapy was effective in patients with EI (treated, 71% survival; untreated, 29%, P=0.02) but not in patients with LI (25% vs. 23%). CONCLUSIONS: Allograft infarcts are associated with AR in 64% of patients, but the AR may be mild. Infarcts are associated with infections. Graft survival is worse in patients with infarcts than in patients with severe AR, consequently these two pathologic diagnoses should not be considered as a single entity.

Adult↗

PubMed1998

Single-center long-term results of renal transplantation for IgA nephropathy.

BACKGROUND: Previous reports with short-term follow-up after renal transplantation for IgA nephropathy (IgAN) have suggested an incidence of recurrence up to 50%, an increased recurrence with living-related donors, and the rarity of graft loss due to recurrence. In this study, the long-term results of renal transplantation for IgAN were examined. METHODS: Between June 1980 and December 1994, 54 patients (61 renal transplants) with end-stage renal disease due to IgA nephropathy were performed at the University of California San Francisco. Actuarial patient and graft survival were compared with a matched reference group. Correlates of recurrent disease (biopsy confirmed) and graft loss were determined. RESULTS: Patient and graft survival for IgA patients were good (100% and 75%, respectively, at 5 years after transplant). Graft survival was lower in IgA recipients with living-related compared with cadaveric renal allografts (P<0.09) and also with renal allografts well matched at HLA-AB (< or =2 AB mismatches) (P<0.09) or HLA-DR (< or =1 mismatch) (P<0.01). Recurrence was not correlated with donor status, recipient age, race, gender, or immunosuppression. Recurrence (18 of 61) resulted in substantial graft loss (6 of 18) or deteriorating renal function (4 of 18) at a mean follow-up of 61 months. Mean time to diagnosis of recurrence and subsequent graft loss was 31 and 63 months, respectively. Despite re-recurrence of IgAN in three of five patients who were retransplanted, all have good long-term renal function. CONCLUSIONS: Substantial graft loss due to recurrent disease after renal transplantation for IgAN occurs with long-term follow-up. Living-related transplantation and HLA matching do not appear to confer an advantage for graft survival in patients with IgAN. Despite the potential for recurrence, IgAN patients enjoy good long-term graft survival.

Actuarial Analysis↗

PubMed1998

In vivo immunogenicity of purified allogeneic hepatocytes in a murine hepatocyte transplant model.

BACKGROUND: It has been reported previously that liver grafts and liver cells seem to be tolerogenic, based on the high frequency of spontaneous tolerance after orthotopic liver transplantation in rodents and on the phenomenon of portal venous tolerance in other models. The purpose of the current study was to characterize in vivo immune responses to allogeneic hepatocytes transplanted into the portal circulation. METHODS: In this functional model of hepatocyte transplantation, "donor" hepatocytes from mice transgenic for human alpha1-antitrypsin (hA1AT) were transplanted by intrasplenic injection into host mice and the secreted hA1AT protein measured in host serum to determine hepatocellular graft survival. Host immune responses were assessed by measurement of donor-specific alloantibodies and delayed-type hypersensitivity responses. In some experiments, liver nonparenchymal cells (NPCs) were co-transplanted with the allogeneic hepatocyte transplant. RESULTS: Allogeneic hepatocyte transplant into immunocompetent hosts resulted in loss of host serum hA1AT by days 7-10 after transplant, whereas syngeneic hosts maintained long-term hepatocellular graft survival as reflected by persistence of serum hA1AT for > 20 weeks. Allogeneic hepatocyte transplantation resulted in the development of donor-specific alloantibody and delayed-type hypersensitivity responses, as well as a "second set" response of accelerated hepatocellular graft rejection after a second transplant. Pretransplantation or co-transplantation of donor-matched liver NPCs at the time of allogeneic hepatocyte transplantation did not prolong hepatocellular allograft survival. CONCLUSIONS: Allogeneic hepatocytes introduced into the portal circulation via intrasplenic injection are immunogenic not tolerogenic and stimulate a weak humoral and strong cell mediated host immune response in vivo. Co-transplantation or pretransplantation of allogeneic liver NPCs did not protect allogeneic hepatocytes from immunologic rejection.

Animals↗

PubMed1998

A functional model of hepatocyte transplantation for in vivo immunologic studies.

BACKGROUND: Previous studies to determine the significant donor and host factors which contribute to immune responses to allogeneic hepatocytes have been pursued with in vitro and in vivo studies. However, in order to further characterize in vivo host immune responses to transplanted hepatocytes in conjunction with their consequences upon allograft survival, a functional model of hepatocyte transplantation in which the function and survival of transplanted hepatocytes could be serially assessed was pursued. METHODS: A transgenic mouse line expressing the human alpha1-antitrypsin (hA1AT) gene was developed in an FVB/N (H2q) mouse (hA1AT-FVB/N). Hepatocytes from these "donor" transgenic mice were transplanted into host mice by intrasplenic injection, and subsequent survival of the transgenic hepatocytes was determined by assay for the secreted hA1AT protein in host serum by enzyme-linked immunosorbent assay. RESULTS: Transplantation of transgenic "donor" hepatocytes (hA1AT-FVB/N) into (a) syngeneic FVB/N (H2q), (b) allogeneic immunoincompetent C57BL/6.SCID (H2b), or (c) allogeneic T cell-deficient (outbred) hosts resulted in long-term survival (> 16 weeks) of hepatocytes. Transplantation of allogeneic hepatocytes (hA1AT-FVB/N, H2q) into C57BL/6 (H2b), C3H (H2k), or BALB/c (H2d) hosts resulted in loss of hA1AT in host serum by day 10 after transplant. Likewise, transplantation of allogeneic hepatocytes into hosts deficient in B cells, CD8+ T cells, or CD4+ T cells resulted in loss of hA1AT by day 10 after transplant. CONCLUSIONS: This functional model of hepatocyte transplantation is validated for the study of host immune responses to hepatocellular grafts and to assess efficacy of strategies designed to alter these in vivo immune responses. The immunologic rejection of allogeneic hepatocytes appears to be T cell-mediated.

Animals↗