Steroid- and ATG-Resistant Rejection After Double Forearm Transplantation Responds to Campath-1H

We herein report on immunological and histological observations in the first bilateral forearm transplant recipient. The last of three rejection episodes occurring on day 95 after transplantation was resistant to steroid and antithymocyte globulin (ATG) treatment. Histology demonstrated lymphocytic infiltrates, apoptotic and necrotic keratinocytes and focal desquamation of the epidermis. Therapy with Campath-1H, however, resulted in complete restitution of normal skin. This is the first report on a successful rescue therapy with Campath-1H in a severe, steroid- and ATG-resistant rejection. Hence, Campath-1H treatment might be a novel and powerful therapeutic option for multiresistant allograft rejection.     

Campath-1H Use in Pediatric Renal Transplantation

Campath-1H is a humanized, monoclonal antibody directed against CD52 determinants on the surface of human B- and T-cells and monocytes. Reports of Campath-1H use as induction in adult renal transplantation have been encouraging with low rejection rates and minimal adverse events. We report four high risk pediatric kidney transplant patients who received Campath-1H for unique indications with variable results. Children ranged in age from 20 months to 16 years. Immunosuppression regimens varied. Three of four patients experienced acute rejection, two of which were C4d positive. Serial flow cytometry was performed on all four patients. The patient who received only Campath-1H has an absolute lymphocyte count that remains less than 50% of baseline at 12-months post-transplant. In addition, in this patient CD3, CD4, CD8 and CD20 remain less than 50% of baseline. From this initial experience using Campath-1H in pediatric renal transplantation we conclude that; (1) the use of Campath-1H does not prevent recurrence of FSGS, (2) as seen in adults, lack of calcineurin inhibition when using Campath-1H may increase the risk of antibody-mediated rejection and (3) prolonged lymphocyte depletion remains even after a single dose of Campath-1H in children.     

Campath-1H Induction Plus Rapamycin Monotherapy for Renal Transplantation: Results of a Pilot Study

Campath-1H, an anti-CD52 monoclonal antibody, was used as induction therapy (40 mg i.v. total dose) in 29 primary human renal transplants, and the patients were maintained on rapamycin monotherapy (levels 8-15 ng/mL) post-transplant. Campath-1H profoundly depletes lymphocytes long-term and more transiently depletes B cells and monocytes. All patients are alive and well at 3-29 months of follow up. One graft was lost because of rejection. There have been no systemic infections and no malignancies. Eight of 29 patients have experienced rejection, which was successfully treated in seven of eight patients. Five of these patients had pathological evidence of a humoral component of their rejection. Seven of the 29 patients were converted to standard triple therapy on account of rejection. Rapamycin was generally well tolerated in that there were no significant wound-healing problems; two lymphoceles required surgical drainage; and most patients were treated with a lipid-lowering agent. Flow crossmatch testing post-transplant revealed evidence of alloantibody in two patients tested with previous combined cellular and humoral rejection. Biopsies have shown no chronic allograft nephropathy to date. In view of the relatively high incidence of early humoral rejection, we plan to modify the immunosuppressive regimen in subsequent pilot studies. This clinical trial provides insight into the use of Campath-1H induction in combination with rapamycin maintenance monotherapy.     

Campath-1H immunosuppressive therapy reduces incidence and intensity of acute rejection in intestinal and multivisceral transplantation

Campath-1H, an anti-CD52 antibody, is being used at our institution as immunosuppression in multivisceral and intestinal transplantation. We reviewed the pathologic findings of 1696 small bowel allograft biopsies obtained in the first 250 days posttransplant from 78 patients who underwent isolated intestinal or multivisceral transplantation and received induction immunosuppression with Campath (n = 30) or Zenapax (n = 57). We found an overall reduced incidence of acute cellular rejection (ACR) in patients receiving Campath (19.1%) compared with those on Zenapax (32.8%). The majority of Campath patients showed no rejection or was indeterminate for rejection over the period of measurement. The frequencies of mild and moderate ACR were approximately twice and three times more common, respectively, in Zenapax-treated patients. The mean grade of ACR in Campath patients compared with Zenapax patients was significantly lower (P <.01) during the first 6 weeks posttransplant. Thereafter, the grade of rejection in both patient groups showed fluctuation, with Zenapax patients sometimes having lower values (eg, at 2 to 4 months) than Campath patients. Patient and graft survival was not significantly different between the two groups. These data suggest that the incidence of ACR is significantly reduced with Campath during the first 2 months posttransplant, when compared with Zenapax. However, the incidence and intensity of ACR following this initial time period shows vacillation with both types of immunosuppression.     

Campath-1H诱导在小肠移植免疫抑制中的作用

目的探讨Campath-1H诱导在小肠移植免疫抑制中的作用。方法回顾性总结1例小肠移植患者的临床资料。结果术中采用Campath-1H静脉注射诱导,术后予以FK506加MMF加激素三联免疫抑制方案。Campath-1H诱导后淋巴细胞及白细胞数目明显减少．经提升白细胞治疗和调整免疫抑制剂用量后逐渐恢复正常。术后早期,患者未发生急性排斥反应及移植物抗宿主病（GVHD）,无严重感染症状,患者顺利渡过围手术期,康复出院。结论Campath-1H术中诱导．术后小剂量FK506加MMF加激素三联免疫抑制方案．可有效控制小肠移植术后早期排斥反应和GVHD的发生。     

Outcomes at 3 years of a prospective pilot study of Campath-1H and sirolimus immunosuppression for renal transplantation

Campath-1H (alemtuzumab) induction was used for renal transplantation in combination with sirolimus as immunosuppression. We previously reported a high (28%) rate of early rejection with this regimen, and now report 3-year outcomes. Twenty-nine patients were recipients of either deceased donor or non-HLA (Human Leukocyte Antigen) identical living donor primary renal allografts. Clinical parameters including infection, malignancy, kidney function, and kidney histology were followed prospectively for 3 years. Three-year cumulative graft and patient survival were 96% and 100%, respectively. Twenty patients were maintained on steroid-free immunosuppressive regimens, and 15 patients were maintained on monotherapy for immunosuppression (12 on sirolimus). No serious infectious complications were observed and two patients developed basal cell skin cancer. The 3-year results of our initial pilot study demonstrate good graft (96%) and patient (100%) outcomes. Campath-1H induction has yielded a high proportion of patients maintained on immunosuppressive monotherapy (57%) without serious infectious- and no malignancy-related complications. The reported regimen yielded novel insights into both Campath-1H and sirolimus therapy in renal transplantation. Because of the higher incidence of early rejection, we recommend a modified strategy of immunosuppression including a brief course of a calcineurin inhibitor.     

Biomarkers of Pulmonary Rejection

Immunologic complications after lung transplantation (LT) include acute cellular rejection (ACR), antibody-mediated rejection (AMR), and most forms of chronic allograft dysfunction (CAD). ACR is an inflammatory process in which the reaction is mediated by the T-cell population. Most episodes of ACR fully recover with treatment, but repeated bouts are considered to be a risk factor for CAD. Biomarker cytokines interleukin (IL)-10, IL-15, IL-6, CCL5, CCR2 and IFNγ may play significant roles in this complication. Formerly bronchiolitis obliterans syndrome (BOS) or chronic rejection or most forms of CAD were considered to be immunologic complications not amenable therapeutic measures. CAD, the main limitation for long-term survival in LT, is characterized histologically by airway epithelial cell apoptosis and luminal fibrosis in the respiratory bronchioles causing airflow obstruction and, in some cases, lung parenchymal affectations causing restrictive lung disease. Several biomarkers have been studied in CAD, IL-6, IL-8, IL-17, IL-23, IL-13, IFN γ, and TGF β cytokines, pH, bile acid, and tripsine of gastroesophageal reflux and toll-like receptors of innate immunity. Herein we have reviewed the literature of biomarkers involved in lung rejection.     

Campath-1H in renal transplantation: The University of Wisconsin experience

BACKGROUND: Immune cell depletion is known to prevent renal allograft rejection and injury. We evaluated the humanized monoclonal antibody Campath-1H (alemtuzumab; ILEX Oncology, San Antonio, Texas) in renal transplant recipients for its safety and efficacy in preventing rejection when used in combination with a calcineurin inhibitor, mycophenolate mofetil, and low-dose steroid therapy. METHODS: One hundred twenty-six consecutive renal allograft recipients received 2 doses of Campath-1H antibody on days 0 and 1. Outcomes were compared to patients who received an anti-CD25 antibody (n=799), Thymoglobulin (n=160), or other antibody treatment (n=156) in combination with a calcineurin inhibitor, mycophenolate mofetil, and higher dose steroids. RESULTS: The Campath-1H group overall experienced less rejection than the other 3 groups (P=.037). Patients with delayed graft function experienced less rejection with Campath-1H than control groups (P=.0096) and improved graft survival (P=.0119). There was no difference in infection or malignancies between the 4 groups. CONCLUSIONS: Campath-1H was well tolerated in renal transplant patients and led to significant reductions in incidence of rejection. Patients with delayed graft function experienced significantly improved graft survival.     

Correlation between human leukocyte antigen antibody production and serum creatinine in patients receiving sirolimus monotherapy after Campath-1H induction

BACKGROUND: In this study, we determined whether Campath-1H induction followed by sirolimus monotherapy inhibited alloantibody production in renal transplantation. Second, we evaluated the correlation between human leukocyte antigen (HLA) antibody production and serum creatinine levels. METHODS: Sera were taken 1 to 24 months after transplantation from 24 patients treated with Campath-1H and sirolimus and tested for serum creatinine and HLA-specific antibody by using flow cytometry and enzyme-linked immunosorbent assay. RESULTS: Ten (42%) of the 24 patients treated with Campath-1H and sirolimus produced HLA antibodies. Six of these 10 developed both donor-specific antibodies (DSAs) and non-donor-specific antibodies (NDSAs), whereas only NDSAs were detected in the other four patients. In patients with biopsy-diagnosed humoral rejection (C4d+), serum levels of both DSA and NDSA significantly correlated with patient serum creatinine levels. Rejection treatment successfully reduced both DSAs and NDSAs and reversed humoral rejection. CONCLUSIONS: The numeric relationship between serum creatinine and DSA levels suggests a causal relationship between alloantibody and transplant rejection.     

Monocyte Infiltration and Kidney Allograft Dysfunction During Acute Rejection

Multiple cell types infiltrate acutely rejecting renal allografts. Typically, monocytes and T cells predominate. Although T cells are known to be required for acute rejection, the degree to which monocytes influence this process remains incompletely defined. Specifically, it has not been established to what degree monocytes impact the clinical phenotype of rejection or how their influence compares to that of T cells. We therefore investigated the relative impact of T cells and monocytes by correlating their presence as measured by immunohistochemical staining with the magnitude of the acute change in renal function at the time of biopsy in 78 consecutive patients with histological acute rejection. We found that functional impairment was strongly associated with the degree of overall cellular infiltration as scored using Banff criteria. However, when cell types were considered, monocyte infiltration was quantitatively associated with renal dysfunction while T-cell infiltration was not. Similarly, renal tubular stress, as indicated by HLA-DR expression, increased with monocyte but not T-cell infiltration. These data suggest that acute allograft dysfunction is most closely related to monocyte infiltration and that isolated T-cell infiltration has less acute functional impact. This relationship may be useful in assigning acute clinical relevance to biopsy findings.     

Intestinal transplantation with alemtuzumab (Campath-1H) induction for adult patients

BACKGROUND: Alemtuzumab (Campath-1H [C1H]) is a humanized monoclonal antibody directed against the CD 52 antigen that is present on the surface of T cells, B cells, natural killer cells and monocytes. We studied its application in intestinal transplantation. METHODS: This is a retrospective review of adult patients who underwent intestinal transplantation between December 1994 and May 2005. Group 1: non-C1H group (n = 39); group 2: C1H group (n = 37). C1H was administered as an induction immunosuppression in four doses (0.3 mg/kg), or in two doses (30 mg/kg). Tacrolimus levels were maintained at low level (5-10 ng/dL). No maintenance steroids were given. RESULTS: One-year survival of group 1 and group 2 patients were 57% and 70%, respectively. This difference is not statistically significant. Of 37 patients in group 2, 21 are alive. The incidence of rejection was lower in group 2 (P < .005). Average current tacrolimus level is 6.97 +/- 3.98 ng/dL. Seventeen patients (81%) are steroid free, and 15 (71%) are maintained solely on tacrolimus. There was no graft versus host disease in group 2. CONCLUSIONS: Our preliminary data suggest that C1H can provide effective immunosuppression for intestinal transplantation. Incidence of rejection was less with this regimen using low maintenance tacrolimus and minimal steroids.     

Time of Occurrence of Kidney Acute Antibody-Mediated Allograft Rejection/Acute Cellular Rejection and Cell Senescence: Implications for Function Outcome

Background

Late versus early acute antibody-mediated rejection (AAMR) or acute cellular rejection (ACR) episodes are associated with poorer kidney function and graft survival. We explored whether cell senescence upon detection of AAMR ± ACR contributes to these results.

Methods

We reviewed the renal transplant database of 2 Institutions. Biopsies performed for acute graft dysfunction from January 2000 to March 2007 were analyzed for morphological criteria of AAMR with or without ACR (n = 17 from 17 patients). Immunoperoxidase staining for p16^INK4B was performed on the remaining paraffin-embedded tissue in 9 of 17 cases. The average number of positive cells/high power field (HPF) was calculated in every case. Cases with rejection were grouped according to the time of presentation: early (<3 months n = 8) versus late (>3 months; n = 9). Graft function was obtained using the Modification of Diet in Renal Disease (mDRD) glomerular filtration rate estimate (eGFR) before, during rejection, and at the last visit, to calculate ΔeGFR.

Results

Nuclear expression of p16^INK4B was 12.2 ± 11.3 cells/HPF in 4 of 8 biopsies performed at a median of 23 (range = 4-80) days (early AAMR ± ACR), and 59.8 ± 51.3 cells/HPF in 5 of 9 biopsies performed at a median of 1171 (range = 279-3210) days (late AAMR ± ACR). eGFR before rejection was 48.5 ± 7.6 mL/min, and 43.7 ± 4.3 mL/min for early and late rejection episodes, respectively (P = not significant [NS]). ΔeGFR of 12.5 ± 25.9 mL/min (early rejection), and −13.7 ± −12.3 mL/min (late rejection), versus last follow-up visit (P = .02) occurred at a median of 143.9 ± 94.1 and 69.6 ± 35.1 weeks after the rejection episodes, respectively.

Conclusions

Even though the number of biopsies analyzed for p16^INK4a was small, it was evident that the number of cells expressing this marker of senescence was higher among biopsy specimens obtained with late rejection episodes. This finding suggests the presence of injuries prior to the rejection episode. The significantly lower eGFR at last follow-up in the late rejection group may translate to a reduced capacity of the repair process to sustain nephron function.     

Campath-1H as rescue therapy for the treatment of acute rejection in kidney transplant patients

INTRODUCTION: Kidney transplant patients with acute rejection episodes refractory to antilymphocyte preparations require aggressive treatment to salvage renal function and reduce the progression of chronic allograft nephropathy. PATIENTS AND METHODS: During a 6-month period, we administered Campath-1H as salvage therapy to five patients who had been previously treated with thymoglobulin and/or OKT3. In addition to measurements of the serum creatinine and BUN levels, we estimated creatinine clearance and glomerular filtration rates (GFR) using the Cockcroft-Gault and the MDRD equations at the time of initiation of therapy as well as at 2 weeks and 2 months thereafter. RESULT: Four of the five patients responded to Campath-1H therapy; kidney function improved to nearly the level before the rejection episode. The estimated creatinine clearance increased approximately threefold and the GFR approximately fourfold higher than the values before Campath-1H administration. The adverse events were mild and self-limited. CONCLUSION: Salvage of refractory acute rejection episodes may be possible in selected patients using Campath-1H.     

Over-Expression of AIF-1 in Liver Allografts and Peripheral Blood Correlates with Acute Rejection after Transplantation in Rats

Early and accurate detection of acute cellular rejection (ACR) is important in the management of liver allograft recipients. We hypothesized that expression of allograft inflammatory factor (AIF)-1 would be associated with liver allograft rejection as previous studies have shown that a relationship exists between kidney and heart transplantation. Indeed using rat orthotopic transplant models we found that the expression of allograft inflammatory factor-1 (AIF-1) can be detected in both allograft and peripheral blood leukocytes with peak levels detected 7 days following liver transplantation. Interestingly, AIF-1 expression increased 2-fold in acutely rejecting liver allografts compared to chronically accepted livers on days 5, 7 and 10 after transplantation. AIF-1 expression in peripheral blood leukocytes was also significantly greater in the rejection model than in the acceptance model. Flow cytometric analysis of peripheral blood leukocytes demonstrated that AIF-1 was expressed in ED2-positive cells, a marker for Kupffer cells. In vitro studies showed that AIF-1 expression in Kupffer cells was up-regulated by coculture with Th1 cytokines. However, neither LPS nor Escherichia coli (E. coli) administration had an affect on AIF-1 expression. These data indicate that high levels of AIF-1 expression reflect aggressive liver allograft rejection and suggest a role for monitoring AIF-1 in peripheral blood leukocytes as a monitor for increased immunosuppression.     

Campath-1H induction and the incidence of infectious complications in adult renal transplantation

BACKGROUND: The purpose of this study was to evaluate adult renal transplantation patients who received a alemtuzumab (Campath-1H)-based induction protocol for the incidence of infectious complications. METHODS: We began using 30 mg Campath-1H intravenously for induction therapy in May 2003. The patients were treated with a maintenance regimen of tacrolimus or mycophenolate mofetil (MMF), and rapidly tapered prednisone; valganciclovir was used for CMV prophylaxis. Forty-nine adult patients who received renal transplants between May 1, 2003 and June 7, 2004 were included. The mean follow-up time was 13.7 months with a range of 10-24 months. Data were collected via a retrospective chart review. RESULTS: The infectious complications noted in the Campath-1H group were compared with a historical group of 56 patients receiving conventional immunosuppression. There was one case of cytomegalovirus (CMV) viremia and two cases of CMV disease (one pneumonitis and one enteritis). There were four cases of urinary tract infection and one extremity cellulitis. One patient developed Cryptococcal meningitis. Eight of the 49 (16%) patients in the Campath group had an infectious complication, compared to 18 out of 56 (32%) in the historical group. CONCLUSION: Campath-1H induction for renal transplantation appears to have a low incidence of associated infectious complications when compared to historical regimens.     

Lower Platelet Count Following Rabbit Antithymocyte Globulin Induction Is Associated With Less Acute Cellular Rejection in Heart Transplant Recipients

BackgroundUnlike lymphodepletion, a decrease in platelet count following induction immunosuppressive therapy with polyclonal rabbit antithymocyte globulin (rATG) is deemed as an adverse event. However, this phenomenon may represent a particular rATG antirejection mechanism.MethodsThis retrospective single-center study included 156 patients who received a heart transplant (HTx) between 2010 and 2018. All patients received rATG induction therapy for 5 days. Absolute lymphocyte count (ALC) and platelet counts were assessed on days 0, 7, and 14 following HTx. The primary outcome of the study was the first occurrence of acute cellular rejection (ACR) defined as grade ≥ 1B within 24 months after HTx.ResultsBoth ALC and platelet counts decreased rapidly after induction. During the 24-month follow-up period, 17% of patients had ACR. Patients with ACR had significantly higher platelet count on day 7 (145 vs 104, P < .001) and higher ALC on day 14 (162 vs 130, P = .035) than those without rejection. Patients in the highest platelet count quartile showed more ACR (50% in quartile 4 vs 0% in quartile 1, P = .006) as well as a higher cumulative total rejection score. Univariate analysis showed that ACR was associated with platelet count on day 7, recipient age, and pretransplant cytomegalovirus IgG serology. In multivariable regression analysis, platelet count on day 7 was the most accurate predictor of ACR.ConclusionsLower platelet count after induction with rATG is associated with less ACR. This suggests platelet involvement in antirejection mechanisms of rATG and a possible rationale for targeting platelets in future immunosuppressive strategies.     

Expression of ICAM-1 and HLA class II in acute cellular and vascular rejection of human kidney allografts

Abstract We studied the relationship between ICAM-1 and class II expression on graft tubular cells and the relationship with graft inflammation in 50 kidney transplants monitored with serial aspiration biopsies after transplantation. Of the 50 grafts, 26 had an acute rejection 17 ± 10 days after transplantation, 5 also had acute vascular rejection (AVR) and 24 had no rejection. The initial post-transplant ICAM-1 and class II expression was low in all grafts. All 21 grafts with acute cellular rejection (ACR) displayed ICAM-1 induction, with a peak at the beginning of acute blastogenic rejection and declining over 20 days to prerejection levels. Class II expression reached a peak later and also declined later to prerejection levels. In the grafts with irreversible AVR both ICAM-1 and class II expression remained elevated. The 24 grafts with no rejection displayed no ICAM-1 or class II induction on tubular cells during the follow-up. The differences between ICAM-1 and classs II expression in biopsies with rejection and with no rejection were statistically significant. The results demonstrate that ICAM-1 was induced early during ACR on the graft tubular cells and that it disappeared rapidly in reversible rejections. The induction of class II antigens was slightly slower but quantitatively greater. In the irreversible rejections with a combination of ACR and AVR both ICAM-1 and class II expression remained elevated.