Viral-specific cytotoxic T-cell responses in HLA-sensitized kidney transplant patients maintained on everolimus and low-dose tacrolimus.

BACKGROUND: Maintenance with "everolimus + reduced dose tacrolimus" (Ev + Taclow ) was reported to reduce the risk of viral infections compared to "tacrolimus + mycophenolate mofetil" (Tac + MMF). Here we examined viremia and viral-specific T-cell (viral-Tc) responses in patients treated with Ev + Taclow versus Tac + MMF in highly-human leukocyte antigen (HLA)-sensitized patients. METHODS: HLA-sensitized (HS) kidney transplant patients were monitored pre- and post-transplant for viremia (cytomegalovirus (CMV), BK, and Epstein-Barr virus (EBV)) by polymerase chain reaction (PCR) in 19 Ev + Taclow and 48 Tac + MMF patients. For CMV PCR analysis, we compared infection rates in 19 Ev + Taclow patients to 48 CMV D+/R- (#28) or CMV D-/R- (#20) Tac + MMF patients. CMV-specific cytotoxic T cell (CMV-Tc) and EBV-specific cytotoxic T cell (EBV-Tc) were evaluated by cytokine flow cytometry, and donor-specific antibody (DSA) levels by Luminex for selected patients in both groups. RESULTS: CMV and EBV viremia rates were similar in Ev + Taclow versus Tac + MMF patients, but BK virus (BKV) rates were significantly higher in Ev + Taclow patients. No patient in either group developed BK virus-associated allograft nephropathy (BKAN) or post-transplant lymphoproliferative disorders (PTLD). CMV-Tc and EBV-Tc decreased significantly after alemtuzumab induction but returned to pre-treatment levels 1-2 months post-transplant in most patients. de novo DSA was similar in both groups as were patient and graft survival and graft rejection. CONCLUSIONS: CMV-Tc and EBV-Tc were similar in Ev + Taclow and Tac + MMF patients. EBV and CMV viremia rates were similar over 1 year. BKV rates were significantly higher in Ev + Taclow patients suggesting no benefit for Ev + Taclow in enhancing viral-Tc effector functions or limiting viral infections.

Belatacept Conversion Protocols and Outcomes in Kidney Transplant Recipients.

BACKGROUND: Conversion from calcineurin inhibitor (CNI)-based to belatacept-based immunosuppression has become common; however, numerous protocols have emerged in lieu of a standardized protocol. The purpose of this study was to characterize belatacept conversion protocols from multiple centers and observe outcomes. METHODS: This was a retrospective study that included Kaiser Permanente Southern California members. The primary outcome was rejection 6 months after conversion and secondary outcomes included change in serum creatinine and graft loss. RESULTS: Seventy-eight patients were included. Thirteen distinct protocols were identified from 8 different transplant centers. Protocols varied by initial dose, induction schedule, and CNI taper. The observed rate of rejection was 6%. There was a trend toward an association of rejection with lower tacrolimus exposure at the time of conversion and lower mycophenolic acid dosing postconversion. Graft survival was 88% and patient survival was 94%. There was a significant improvement in creatinine after conversion. Those with early conversions and creatinine >2.0 mg/dL at the time of conversion had the best response. CONCLUSIONS: A large variety of belatacept conversion protocols were identified. Protocols were defined by the initial dose, induction regimen, and CNI taper. Rejection rates were low and may be influenced by exposure to maintenance immunosuppression during and after conversion. Most patients showed stabilization and improvement in creatinine postconversion, with the largest effect in those with an early conversion and serum creatinine >2.0 mg/dL.

Plasma Exosomes From HLA-Sensitized Kidney Transplant Recipients Contain mRNA Transcripts Which Predict Development of Antibody-Mediated Rejection.

BACKGROUND: Sensitization to HLA remains a significant immunologic barrier to successful transplantation. Identifying immune mechanisms responsible for antibody-mediated rejection (AMR) is an important goal. Here, we explored the possibility of predicting the risk for AMR by measuring mRNA transcripts of AMR-associated genes in plasma exosomes from kidney transplant patients. METHODS: Total RNA was extracted from exosomes purified from 152 ethylenediaminetetraacetic acid-plasma samples of 64 patients (18 AMR, 8 cell-mediated rejection [CMR], 38 no rejection in desensitized [DES] and non-DES control groups) for reverse transcription into cDNA, preamplification and then real time quantitative polymerase chain reaction (qPCR) for 21 candidate genes. The mRNA transcript levels of each gene were calculated. Comparisons were made among 4 patient groups for each gene and also for a gene combination score based on selected genes. RESULTS: Among 21 candidate genes, we identified multiple genes (gp130, CCL4, TNFα, SH2D1B, CAV1, atypical chemokine receptor 1 [duffy blood group]) whose mRNA transcript levels in plasma exosomes significantly increased among AMR compared with CMR and/or control patients. A gene combination score calculated from 4 genes of gp130, SH2D1B, TNFα, and CCL4 was significantly higher in the AMR than the CMR (P < 0.0001) and no rejection control groups (P < 0.01 vs DES control, P < 0.05 vs non-DES control). CONCLUSIONS: Our results suggest that plasma exosomes may contain information indicating clinical conditions of kidney transplant patients. mRNA transcript profiles based on gp130, SH2D1B, TNFα, and CCL4 in plasma exosomes may be used to predict on-going and/or imminent AMR.

Impact of Desensitization on Antiviral Immunity in HLA-Sensitized Kidney Transplant Recipients.

Viral infections represent significant morbidity and mortality factors in kidney transplant recipients, with CMV, EBV, and BKV infections being most common. Desensitization (DES) with IVIg and rituximab with/without plasma exchange followed by kidney transplantation with alemtuzumab induction increased successful transplant rates in HLA-sensitized patients but may represent an increased risk for viral infections due to severe lymphocyte depletion. Here, we report on the posttransplant viral infection status in 372 DES versus 538 non-DES patients. CMV and EBV viremia were significantly lower in DES patients, while BKV viremia was similar. This trend was observed primarily in CMV sero(-), EBV sero(+), and sero(-) patients. No patient developed PTLD. The incidence of BKAN, allograft, and patient survival was similar in both groups. These viral infections were not associated with subsequent allograft rejection which occurred within 6 months after the infection. Conclusions. The IVIg + rituximab desensitization combined with alemtuzumab induction with triple immunosuppression maintenance does not increase the risk for CMV, EBV, and BKV infections. Possible factors include, in addition to posttransplant antiviral prophylaxis and PCR monitoring, presence of memory T cells and antibodies specific to CMV and likely EBV, NK cell-mediated ADCC despite lymphocyte depletion, elimination of EBV and CMV reservoirs by rituximab and alemtuzumab, and use of IVIg with antiviral properties.

Differences in pathologic features and graft outcomes in antibody-mediated rejection of renal allografts due to persistent/recurrent versus de novo donor-specific antibodies.

Antibody-mediated rejection (ABMR) of renal allografts occurs in two forms. Type 1 ABMR results from persistence and/or a rebound of preexisting donor-specific antibodies in sensitized patients and usually occurs early post-transplantation. Type 2 ABMR is associated with de novo donor-specific antibodies and usually occurs over one year post-transplantation. It is generally accepted that types 1 and 2 also differ with regard to certain pathologic features including the frequencies of C4d positivity and concurrent cell-mediated rejection. However, direct comparison of pathologic, serologic, and clinical features of types 1 and 2 ABMR is lacking. Here we compared these features in 80 cases of ABMR (37 type 1, 43 type 2) diagnosed at our center. Compared with type 1, type 2 ABMR occurred later post-transplantation, was more often associated with donor-specific antibodies against Class II HLA, and was associated with more interstitial fibrosis/tubular atrophy and more frequent cell-mediated rejection, although these did not differ with respect to C4d positivity. By univariate analysis, graft survival was lower with type 2 than type 1 ABMR with borderline significance. Still, among these 80 patients, all but one treated for ABMR following diagnosis, the only two independent predictors of graft failure were at least moderate interstitial fibrosis/tubular atrophy and failure of the donor-specific antibody relative intensity scale score, a measure of the combined strength of all donor-specific antibodies present, to decrease in response to therapy.

Six-year outcomes in broadly HLA-sensitized living donor transplant recipients desensitized with intravenous immunoglobulin and rituximab.

Desensitization with intravenous immunoglobulin (IVIG) and rituximab can improve transplantation rates in broadly sensitized kidney transplant recipients. However, long-term outcomes are lacking. Here we analyze long-term outcomes in living donor kidney transplant recipients desensitized with this regimen and compare them to low-risk recipients. Living donor kidney transplants that took place between July 2006 and December 2010 were considered retrospectively. The primary end point of the study was death-censored allograft survival at last follow-up. Secondary end points included patient survival, incidence of rejection, glomerular filtration rate (GFR), and proteinuria. There were 66 sensitized and 111 low-risk patients included. Average follow-up was 68 months. There was no difference in long-term patient or graft survival. The rate of rejection was similar in the groups with more early rejection in the sensitized group and more late rejection in the low-risk group. There was more antibody-mediated rejection in the sensitized group. Estimated GFR was similar during the follow-up period. Risk factors for rejection included a positive cross-match (HR: 2.4 CI: 1.35-4.40) and age (HR: 0.97 CI: 0.95-0.99). Desensitization with IVIG and rituximab has good long-term results with graft outcomes similar to non-HLA-sensitized patients despite higher immunologic risk.

Risk factors associated with the development of histocompatibility leukocyte antigen sensitization.

PURPOSE OF REVIEW: Despite excellent short-term kidney allograft survival rates, long-term outcomes have not improved. For years, the focus on improving these outcomes revolved around minimization or elimination of calcineurin toxicity. Despite our best efforts, approximately 5000 allografts are lost each year in the United States and results in a significant emotional burden for patients and financial burden for the healthcare system. RECENT FINDINGS: Advancements in detection of donor-specific histocompatibility leukocyte antigen antibodies (DSAs) and improved assessment of allograft biopsy tissue have shown that the most common cause for graft failures is DSA-related antibody-mediated rejection. Sensitization is directly related to human tissue exposure prior to transplant. We now know that sensitization can occur in patients who are non compliant or poorly compliant with their calcineurin inhibitors. They develop de-novo DSAs, which are responsible for numerous allograft losses around the world. SUMMARY: Given the current evidence, it is imperative that all transplant physicians recognize the importance of encouraging medication adherence to prevent the consequences of DSA-induced graft failure. However, little progress has been made in this area. Other potential therapeutic approaches based on B-cell depletion or modulation early posttransplant may help to reduce the risk for de-novo DSA development.

Modern approaches to incompatible kidney transplantation.

The presence of human-leukocyte antigen (HLA)-antibodies and blood group incompatibility remain a large barrier to kidney transplantation leading to increased morbidity and mortality on the transplant waiting list. Over the last decade a number of new approaches were developed to overcome these barriers. Intravenous immunoglobulin (IVIG) remains the backbone of HLA desensitization therapy and has been shown in a prospective, randomized, placebo controlled trial to improve transplantation rates. Excellent outcomes with the addition of rituximab (anti-B cell) to IVIG based desensitization have been achieved. There is limited experience with bortezomib (anti-plasma cell) and eculizumab (complement inhibition) for desensitization. However, these agents may be good adjuncts for patients who are broadly sensitized with strong, complement-fixing HLA antibodies. Excellent short and long-term outcomes have been achieved in ABO incompatible transplantation with the combination of antibody removal, B cell depletion, and pre-transplant immunosuppression. Kidney paired donation has emerged as a reasonable alternative for programs who cannot provide desensitization or in conjunction with desensitization. Future therapies directed toward cytokines that alter B cell proliferation are under investigation.

A Phase I/II Trial of the Interleukin-6 Receptor-Specific Humanized Monoclonal (Tocilizumab) + Intravenous Immunoglobulin in Difficult to Desensitize Patients.

BACKGROUND: Current desensitization (DES) methods are not always effective. Thus, novel, more effective approaches are desirable. Interleukin (IL)-6 is an attractive target as it promotes B-cell differentiation to plasma cells, is important for immunoglobulin production, and induces Th17 cells. Here, we undertook a phase I/II pilot study of DES using a novel drug (anti-IL-6 receptor (IL-6R),Tocilizumab [TCZ]) + intravenous Ig (IVIg) to assess safety and limited efficacy. METHODS: From July 2012 to November 2013, 10 patients unresponsive to DES with IVIg + Rituximab were treated with IVIg + TCZ. Patients received IVIg on days 0 and 30 at 2 g/kg and TCZ 8 mg/kg on day 15 then monthly for 6 months. If transplanted, patients received IVIg once and TCZ monthly for 6 months. RESULTS: No differences in baseline characteristics were seen in patients not transplanted versus transplanted. Two patients in each group developed serious adverse events: not transplanted- pulmonary congestion with epilepticus (likely not related) versus transplanted infective colitis with colonic perforation and Bell Palsy (both possibly related). Five of 10 patients were transplanted. Mean time to transplant from first DES was 25 +/- 10.5 months but after TCZ was 8.1 +/- 5.4 months. Six-month protocol biopsies showed no antibody-mediated rejection. Donor-specific antibody strength and number were reduced by TCZ treatment. Renal function at 12 months was 60 +/- 25 mL/min. CONCLUSIONS: Tocilizumab and IVIg appear to be safe. From this pilot trial, we are cautiously optimistic that targeting the IL-6/IL-6R pathway could offer a novel alternative for difficult to desensitize patients. Larger controlled studies are essential to prove efficacy

A phase I/II placebo-controlled trial of C1-inhibitor for prevention of antibody-mediated rejection in HLA sensitized patients.

BACKGROUND: Antibody-mediated rejection (AMR) is a severe form of rejection, mediated primarily by antibody-dependent complement (C) activation. C1 inhibitor (C1-INH, Berinert) inhibits the classical and lectin pathways of C activation. We performed a randomized, placebo-controlled study using C1-INH in highly sensitized renal transplant recipients for prevention of AMR. METHODS: Twenty highly sensitized patients desensitized with IVIG+rituximab±plasma exchange were enrolled and randomized 1:1 to receive plasma-derived human C1-INH (20 IU/kg/dose) versus placebo intraoperatively, then twice weekly for 7 doses. Renal function, adverse events (AEs)/serious AEs, C3, C4, and C1-INH levels were monitored and C1q+ HLA antibodies were also blindly assessed. RESULTS: One patient in the C1-INH group versus 2 patients in the placebo group developed serious AEs, but none were related to study drug. Delayed graft function developed in 1 C1-INH subject and 4 in the placebo. The C1-INH trough levels increased with C1-INH treatment. C3 and C4 levels also increased significantly in the C1-INH group compared to placebo. No C1-INH patient developed AMR during the study. Two patients developed AMR after the study. Three placebo patients developed AMR, one during the study. C1q+ donor specific antibodies were reduced in 2 C1-INH treated patients tested, while immunoglobulin G DSA levels showed decreased binding for both groups. CONCLUSIONS: The C1-INH appears safe in the posttransplant period. The C1-INH treatment may reduce ischemia-reperfusion injury. The C1-INH also resulted in significant elevations of C1-INH levels, C3, C4, and reduced C1q+ HLA antibodies. Taken together, the combination of antibody reduction and C1-INH may prove useful in prevention of AMR. Further controlled studies are warranted.

Factors Predicting Risk for Antibody-mediated Rejection and Graft Loss in Highly Human Leukocyte Antigen Sensitized Patients Transplanted After Desensitization.

BACKGROUND: Desensitization with intravenous immunoglobulin and rituximab (I+R) significantly improves transplant rates in highly sensitized patients, but antibody-mediated rejection (ABMR) remains a concern. PATIENTS AND METHODS: Between July 2006 and December 2012, 226 highly sensitized patients received transplants after desensitization. Most received alemtuzumab induction and standard immunosuppression. Two groups were examined: ABMR (n = 181) and ABMR (n = 45, 20%). Risk factors for ABMR, pathology, and outcomes were assessed. RESULTS: Significant risks for ABMR included previous transplants and pregnancies as sensitizing events, donor-specific antibody (DSA) relative intensity scores greater than 17, presence of both class I and II DSAs at transplant and time on waitlist. The ABMR showed a significant benefit for graft survival and glomerular filtration rate at 5 years (P < 0.0001). Banff pathology characteristics for ABMR patients with or without graft loss did not differ. C4d versus C4d ABMR did not predict graft loss (P = 0.086). Thrombotic microangiopathy (TMA) significantly predicted graft failure (P = 0.045). The ABMR episodes were treated with I+R (n = 25), or, in more severe ABMR, plasma exchange (PLEX)+I+R (n = 20). Graft survival for patients treated with I+R was superior (P = 0.028). Increased mortality was seen in ABMR patients experiencing graft loss after ABMR treatment (P = 0.004). The PLEX + Eculizumab improved graft survival for TMA patients (P = 0.036). CONCLUSION: Patients desensitized with I+R who remain ABMR have long-term graft and patient survival. The ABMR patients have significantly reduced graft survival and glomerular filtration rate at 5 years, especially TMA. Severe ABMR episodes benefit from treatment with PLEX + Eculizumab. The DSA-relative intensity scores at transplant was a strong predictor of ABMR. Donor-specific antibody avoidance and reduction strategies before transplantation are critical to avoiding ABMR and improving long-term outcomes.

Immunologic and Infectious Complications in Highly Sensitized Patients Post-Kidney Transplantation.

Desensitization therapies evolved more than a decade ago to deal with the growing numbers of highly human leukocyte antigen sensitized patients who have an immunologic barrier to successful transplantation. Two protocols have evolved and have been adopted for primary desensitization. These include high dose intravenous immune globulin (IVIG), plasma exchange + low doses IVIG +/- rituximab. These protocols have been very successful and have extended and improved the lives of numerous sensitized patients who would otherwise languish on dialysis. Despite these successes, problems do exist with desensitization. These include the risks for antibody-mediated rejection (ABMR) and infections related to increased immunosuppression. Here, we discuss current and evolving therapies for the prevention and treatment of ABMR. In addition, we discuss current data regarding infection risks, especially BK virus, that may predispose patients to development of de novo donor specific antibodies and antibody rejection. Novel therapies will also be discussed.

Benefits of rituximab combined with intravenous immunoglobulin for desensitization in kidney transplant recipients.

BACKGROUND: Highly HLA-sensitized (HS) patients have difficulty accessing compatible donors, especially deceased donor (DD) transplants. Desensitization protocols (DES) have evolved, but rigorous evaluation is lacking. Here, we examined the efficacy of rituximab as a DES agent in a placebo-controlled trial. METHODS: Candidates were randomized to IVIG+placebo versus IVIG+rituximab. End points included rates of transplantation, antibody-mediated rejection (ABMR), and renal function. Protocol biopsies were performed at 1 year and analysis of patient and graft survival and donor-specific HLA antibodies (DSA) were performed. RESULTS: Initially, 15 HS DDs were randomized with 13 receiving transplants. However, we discontinued study entry after five serious adverse events were observed. The study was un-blinded and attribution of patients was noted (IVIG+placebo N=7, IVIG+rituximab N=6). No significant differences were seen in DSA levels at transplant. All ABMR episodes occurred in the IVIG+placebo arm and required intense therapy (P=0.06). The two graft losses were in the placebo group. DSA rebound associated with severe ABMR was seen in three patients in the IVIG+placebo group. No rebound was seen in the IVIG+rituximab group. Renal function at 6 and 12 months showed a significant benefit for IVIG+rituximab (P=0.04). CONCLUSIONS: Based on limited assessment with acknowledged limitations, both protocols appear effective in achieving levels of DSA allowable for transplantation. However, IVIG+rituximab appeared more effective in preventing DSA rebound and, more importantly, preventing ABMR and development of transplant glomerulopathy.

Polyomavirus BK viremia in kidney transplant recipients after desensitization with IVIG and rituximab.

BACKGROUND: Desensitization with intravenous immune globulin (IVIG) and rituximab improves transplantation rates. It is unclear if desensitization increases the risk of polyomavirus BK (BKV) viremia. Here, BKV viremia in HLA-sensitized patients after desensitization with IVIG and rituximab was analyzed. METHODS: Baseline characteristics and outcomes were compared in the desensitized group (N=187) and the non-desensitized group (N=284). Surveillance for BKV viremia was done at 1, 2, 3, 6, 9, and 12 months posttransplant. Univariable and multivariable analyses were performed. RESULTS: BKV viremia was observed in 20% of the desensitized and 10% of the non-desensitized (P<0.001) groups by 2 years posttransplant. The desensitized group had more lymphocyte depleting induction and more rejection. They also had a greater degree of viremia with more patients having a peak viral load greater than 10,000 copies per milliliter (P<0.001). However, there was no significant difference in BKV-associated nephropathy or graft loss in the two groups. There was an association of BKV viremia with desensitization and lymphocyte induction. Only desensitization remained a significant predictor in the multivariable model with an adjusted HR of 2.13 (95% CI 1.21-3.77, P=0.009). CONCLUSIONS: Desensitization with IVIG and rituximab is associated with a higher incidence of BKV viremia with high viral copies and was the major predictor of BKV viremia in the multivariable model. More frequent surveillance for BKV viremia and an early, aggressive treatment strategy are essential for preventing high BKV viral loads in this patient population.

Histopathologic features of transplant glomerulopathy associated with response to therapy with intravenous immune globulin and rituximab.

Transplant glomerulopathy (TG) is associated with poor long-term allograft survival and is often accompanied by microcirculation inflammation. Histopathologic scoring may inform prognosis and help guide therapy. We retrospectively assessed 33 patients with biopsy-proven TG. All biopsies were given a glomerulitis (g) and peritubular capillaritis (ptc) score. We determined allograft survival and serum creatinine stability in three different score groups: g < 2 and ≥ 2, ptc < 2 and ≥ 2, and (g + ptc) < 4 and ≥ 4. We assessed the impact of treatment with intravenous immune globulin (IVIG) and rituximab on outcomes. Graft survival and serum creatinine stability did not differ in each of the histopathologic score groups. Higher-score groups were associated with the presence of concomitant antibody-mediated rejection and were more likely to receive IVIG and rituximab. Treatment with IVIG and rituximab resulted in stability of serum creatinine within the higher-score groups, but not in the lower-score groups. Stabilization of serum creatinine was associated with an improvement in donor-specific antibody. Histopathologic scoring in kidney allograft biopsies with TG may help guide treatment. The combination of IVIG and rituximab appears to be beneficial in patients whose biopsies have moderate or severe microvascular injury.

Efficacy, outcomes, and cost-effectiveness of desensitization using IVIG and rituximab.

BACKGROUND: Transplantation rates are very low for the broadly sensitized patient (panel reactive antibody [PRA]>80%; HS). Here, we examine the efficacy, outcomes, and cost-effectiveness of desensitization using high-dose intravenous immunoglobulin (IVIG) and rituximab to improve transplantation rates in HS patients. METHODS: From July 2006 to December 2011, 207 HS (56 living donors/151 deceased donors) patients (donor-specific antibody positive, PRA>80%) were desensitized using IVIG and rituximab. After desensitization, responsive patients proceeded to transplantation with an acceptable crossmatch. Cost and outcomes of desensitization were compared with dialysis. RESULTS: Of the 207 treated patients, 146 (71%) were transplanted. At 48 months, patient and graft survival by Kaplan-Meier were 95% and 87.5%, respectively. The total 3-year cost for patients treated in the desensitization arm was $219,914 per patient compared with $238,667 per patient treated in the dialysis arm. Thus, each patient treated with desensitization is estimated to save the U.S. healthcare system $18,753 in 2011 USD. Overall, estimated patient survival at the end of 3 years was 96.6% for patients in the desensitization arm of the model (based on Cedars-Sinai survival rate) compared with 79.0% for an age, end-stage renal disease etiology, and PRA matched group of patients remaining on dialysis during the study period. CONCLUSIONS: We conclude that desensitization with IVIG+rituximab is clinically and cost-effective, with both financial savings and an estimated 17.6% greater probability of 3-year survival associated with desensitization versus dialysis alone. However, the benefits of desensitization and transplantation are limited by organ availability and allocation policies.

Infectious complications in kidney-transplant recipients desensitized with rituximab and intravenous immunoglobulin.

BACKGROUND AND OBJECTIVES: Rituximab and intravenous Ig (IVIG) are commonly used for desensitization of HLA and blood group-incompatible (ABOi) transplants. However, serious infections have been noted in association with rituximab administration. In this study, we retrospectively compared infectious outcomes in those who received rituximab plus IVIG for HLA or ABOi transplants (RIT group) with a group of nonsensitized, ABO-compatible transplant recipients (non-RIT group). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Patients undergoing kidney transplantation at Cedars-Sinai Medical Center were included in the analysis. A total of 361 patients were identified. All received antimicrobial prophylaxis and viral surveillance. The primary outcome was infection. RESULTS: Overall patient survival was 97 and 96%, and graft survival was 91 and 89% in the RIT and non-RIT groups, respectively, after an average follow-up of 18 months. There were equal rates of bacterial (34.7% versus 39.1%), viral (21.8% versus 25.1%), fungal (5.9% versus 5.2%), and serious infections (22.9% versus 25.5%) in the RIT and non-RIT groups respectively. Urinary tract infection was the most common infection, accounting for 50% of all bacterial infections. Cytomegalovirus viremia was nonsignificantly more common in the nonrituximab-treated group (15.2% versus 10%), whereas BK viremia was marginally more frequent in the rituximab-treated group (10.6% versus 5.8%). There were no graft losses caused by BK-associated nephropathy. There were two deaths in each group related to infection (1%). CONCLUSION: Rituximab does not increase infection risk when used with intravenous Ig for desensitization.

B-cell immunotherapeutics: emerging roles in solid organ transplantation.

PURPOSE OF REVIEW: The introduction of B-cell-directed therapies for autoimmune diseases illuminated the biologic relevance of B cells in mediation of autoimmunity. They have also rejuvenated interest in how B cells mediate multiple effector functions that include antibody production, antigen presentation to T cells, costimulation and the production of immune stimulating and immune modulatory cytokines. These advances clearly have implications for patients receiving solid organ transplants, especially those who are ABO incompatible, sensitized to human leukocyte antigen (HLA) pretransplant, or develop anti-HLA antibodies posttransplant. RECENT FINDINGS: Here, we will review the current and evolving agents developed for B-cell depletion or modulation and discuss their potential for modification of alloimmunity in transplant recipients. We will focus on data from humans and animal models in which B cells and antibodies are targeted to reduce inflammation in transplantation. This will include a review of the immunomodulatory drug intravenous immunoglobulin, anti-CD20 (rituximab) where more clinical experience has been reported. Finally, we will discuss emerging B-cell-directed therapies which include those directed at the B-cell activating factor of the tumor necrosis family/A proliferation inducing ligand, anti-CD22, newer anti-CD20 monoclonals and antibodies to the interleukin 6 receptor (tocilizumab). SUMMARY: The primary objective of this review is to define the critical role of B cells in development of alloimmunity and how this can be modified by B-cell-directed therapies.

Immunologic parameters and viral infections in patients desensitized with intravenous immunoglobulin and rituximab.

Desensitization with IVIG and rituximab followed by transplantation with alemtuzumab or daclizumab induction is an effective clinical protocol. Here, we examined the effects of this protocol on immune cell number, T cell function by Cylex ImmuKnow®, CMV-specific CD8+ T cell (CMV-Tc) activity, total and viral-specific immunoglobulin levels and viral infections. In 17 highly HLA-sensitized (HS) patients who received desensitization, CD19+ cells were undetectable immediately after desensitization, while other immune cells were unchanged. No alteration in Cylex or CMV-Tc levels was seen. In separate 14 HS patients who were desensitized followed by transplantation, T cell numbers were near zero after alemtuzumab, while NK cell reduction was minimal. Early B cell recovery was not a risk for antibody-mediated rejection. Total IgG, IgM, and IgA remained in the normal range up to 12.6 months post-transplant, and CMV IgG level did not change. CMV-Tc activity was eliminated post-transplant in some patients, but recovered by 4 months post-transplant. None of them developed CMV infection. In conclusion, IVIG-rituximab-desensitization does not significantly alter T cell function pre-transplant, or reduce Ig levels below the normal range post-transplant. Although post-transplant induction therapy is associated with a transient depletion of viral-specific CD8+ memory cells, it does not increase risks for viral infections.