Progressive multifocal leukoencephalopathy after fingolimod treatment.

OBJECTIVE: We describe the characteristics of the 15 patients with fingolimod-associated progressive multifocal leukoencephalopathy (PML) identified from the Novartis data safety base and provide risk estimates for the disorder. METHODS: The Novartis safety database was searched for PML cases with a data lock point of August 31, 2017. PML classification was based on previously published criteria. The risk and incidence were estimated using the 15 patients with confirmed PML and the overall population of patients treated with fingolimod. RESULTS: As of August 31, 2017, 15 fingolimod-treated patients had developed PML in the absence of natalizumab treatment in the preceding 6 months. Eleven (73%) were women and the mean age was 53 years (median: 53 years). Fourteen of the 15 patients were treated with fingolimod for >2 years. Two patients had confounding medical conditions. Two patients had natalizumab treatment. This included one patient whose last dose of natalizumab was 3 years and 9 months before the diagnosis of PML. The second patient was receiving fingolimod for 4 years and 6 months, which was discontinued to start natalizumab and was diagnosed with PML 3 months after starting natalizumab. Absolute lymphocyte counts were available for 14 of the 15 patients and none exhibited a sustained grade 4 lymphopenia (≤200 cells/µL). CONCLUSIONS: The risk of PML with fingolimod in the absence of prior natalizumab treatment is low. The estimated risk was 0.069 per 1,000 patients (95% confidence interval: 0.039-0.114), and the estimated incidence rate was 3.12 per 100,000 patient-years (95% confidence interval: 1.75-5.15). Neither clinical manifestations nor radiographic features suggested any unique features of fingolimod-associated PML.

Dual effects of the alloresponse by Th1 and Th2 cells on acute and chronic rejection of allotransplants.

The contribution of direct and indirect alloresponses by CD4(+) Th1 and Th2 cells in acute and chronic rejection of allogeneic transplants remains unclear. In the present study, we addressed this question using a transplant model in a single MHC class I-disparate donor-recipient mouse combination. BALB/c-dm2 (dm2) mutant mice do not express MHC class I L(d) molecules and reject acutely L(d+) skin grafts from BALB/c mice. In contrast, BALB/c hearts placed in dm2 mice are permanently accepted in the absence of chronic allograft vasculopathy. In this model, CD4(+) T cells are activated following recognition of a donor MHC class I determinant, L(d) 61-80, presented by MHC Class II A(d) molecules on donor and recipient APC. Pre-transplantation of recipients with L(d) 61-80 peptide emulsified in complete Freund's adjuvant induced a Th1 response, which accelerated the rejection of skin allografts, but it had no effect on cardiac transplants. In contrast, induction of a Th2 response to the same peptide abrogated the CD8(+) cytotoxic T cells response and markedly delayed the rejection of skin allografts while it induced de novo chronic rejection of heart transplants. This shows that Th2 cells activated via indirect allorecognition can exert dual effects on acute and chronic rejection of allogeneic transplants.

Chemokines and diseases.

Chemokines are a group of small, pro-inflammatory molecules first described for their pivotal role in the mobilization of specific leukocyte subsets towards sites of inflammation and their activation once they arrive. They have now emerged as key regulators in the development, differentiation and anatomic distribution of inflammatory cells. Chemokines also orchestrate both the innate immune response and antigen specific immunity through their coordination of dendritic cells and lymphocytes. Due to their vast functional responsibilities, they are linked to the pathogenesis of many seemingly unrelated diseases that include HIV infection, cancer, atherosclerosis, autoimmune diseases, graft rejection and dermatological disorders. This review focuses on the physiology of chemokines and their significant roles in the pathogenesis and progression of major diseases.

Correlation between glomerular size and long-term renal function in patients with substantial loss of renal mass.

PURPOSE: Focal segmental glomerulosclerosis and progressive renal failure have been reported in reduced renal mass models. However, these findings are not consistent across all species. Increased intracapillary pressure and chronic glomerular hyperfiltration have been shown to contribute to this progression. Studies also have shown that a strong correlation exists between higher glomerular size and the degree of glomerular sclerosis that develops following loss of functioning nephrons. MATERIALS AND METHODS: To evaluate the relationship between glomerular size and long-term renal function following massive renal mass removal we describe 9 patients with less than 50% renal mass. All patients had undergone initial nephrectomy followed by partial second nephrectomy, with 30% to 50% of the second kidney excised for localized tumor. RESULTS: In 3 patients moderate to severe renal failure developed. Mean planar glomerular area (MPA) was 29.45 +/- 2.2 mm3 for all patients. Multivariate linear regression analysis demonstrated a significant association between MPA 30 mm3 or greater and increased serum creatinine. For patients with MPA 30 mm3 or greater the predicted delta creatinine was 2.43 mg/dl higher than that in patients with MPA less than 30 mm3 (p = 0.0028). Age was the only other covariate significantly associated with outcome in multivariate analysis. CONCLUSIONS: Our data indicate an individual susceptibility toward developing renal failure after significant renal mass reduction. We suggest that patients with less than 50% renal mass and higher MPA are at greater risk for progressive renal failure. MPA may be used as a marker in high risk patients with substantial loss of renal mass to predict long-term renal function.

T-cell response to cardiac myosin persists in the absence of an alloimmune response in recipients with chronic cardiac allograft rejection.

BACKGROUND: Immune-mediated injury to the graft has been implicated in the pathogenesis of chronic rejection. However, little is known regarding the nature of the antigen(s) involved in this immune process. We demonstrated that cardiac transplantation in mice induces an autoimmune T-cell response to a heart tissue-specific protein, cardiac myosin (CM). This response contributes to transplant rejection in that its modulation affects cardiac graft survival. This study investigates whether anti-CM T cells undergo activation and expansion in mice with chronic cardiac allograft rejection. METHODS: The frequency of CM- and donor major histocompatibility complex (MHC)-specific interferon (IFN)-gamma-producing T cells were assessed by ELISPOT in BALB/c mice, which were injected with anti-CD40L (MR1) mAb (chronic rejection group) or CTLA4Ig fusion protein (tolerant group) and transplanted with C57BL/6 cardiac allografts. RESULTS AND CONCLUSIONS: MR1-treated BALB/c recipients of C57BL/6 hearts with chronic rejection displayed a high frequency of activated CM-specific T cells, whereas the frequency of activated alloreactive T cells were similar to naïve, nontransplanted mice. In contrast, no activation of CM-reactive T cells was detected in tolerant recipients after CTLA4Ig treatment. Therefore, in the absence of alloimmunity, chronic rejection is associated with persistence of a T-cell response against CM. Our data indicate that anti-CM autoimmunity may be involved in the immune mechanisms of chronic rejection and suggest that tolerance strategies should target both allo- and autoimmune responses to prevent this process.

Angiotensin II receptor blocker-associated angioedema: on the heels of ACE inhibitor angioedema.

Angioedema and cough are known side effects of angiotensin-converting enzyme (ACE) inhibitors. Angiotensin-converting enzyme is a potent inhibitor of kinase II, which facilitates the breakdown of bradykinin. An increase in bradykinin levels results in continued prostaglandin E2 synthesis, vasodilation, increased vascular permeability, and increased interstitial fluid. In contrast, the angiotensin II receptor blockers (ARBs) do not increase bradykinin levels. Angioedema as a complication of ACE inhibitor therapy is not widely recognized; this complication is even less recognized with second-line ARBs. We report angioedema associated with losartan (an ARB) in a patient who had experienced angioedema secondary to enalapril (an ACE inhibitor). Almost half of patients with ARB-associated angioedema also had developed angioedema while receiving ACE inhibitor therapy. Clinicians should exercise caution when using ARBs in patients with a history of angioedema secondary to ACE inhibitors.

Modulation of tissue-specific immune response to cardiac myosin can prolong survival of allogeneic heart transplants.

The role of immune response to tissue-specific Ags in transplant rejection is poorly defined. We have previously reported that transplantation of cardiac allografts triggers a CD4(+) Th1 cell response to cardiac myosin (CM), a major contractile protein of the heart, and that pretransplant activation of proinflammatory CM-specific T cells accelerates rejection. In this study, we show that administration of CM together with IFA (CM/IFA) can prevent acute rejection of an allogeneic heart transplant. Prolongation of cardiac graft survival is associated with activation of CM- and allo-specific T cells secreting type 2 cytokines (IL-4, IL-5) and reduction of the frequency of proinflammatory IFN-gamma-secreting (type 1) alloreactive T cells. Blocking of IL-4 cytokine with Abs abrogates the prolongation. CM/IFA treatment prevents acute rejection of MHC class I-mismatched, but not fully mismatched grafts. However, if donor heart is devoid of MHC class II expression, CM-IFA administration delays rejection of fully allogeneic cardiac transplants. This finding suggests that the effect of CM modulation depends on the type (direct vs indirect) and strength of recipient's CD4(+) T cell alloresponse. Our results underscore the important role of host immunity to tissue-specific Ags in the rejection of an allograft. This study demonstrates that modulation of the immune response to a tissue-specific Ag can significantly prolong cardiac allograft survival, an observation that may have important implications for the development of novel selective immune therapies in transplantation.

A novel CD154 monoclonal antibody in acute and chronic rat vascularized cardiac allograft rejection.

BACKGROUND: The CD40-CD154 interaction is critically important in the cell-mediated immune responses. Blockade of this costimulatory pathway has been shown to prevent acute allograft rejection in murine, as well as nonhuman primate models. However, the role of the CD40-CD154 pathway in the development of chronic rejection and the effects of CD154 targeting on progression of chronic rejection have not been evaluated. METHODS: We examined the effect of AH.F5, a new hamster anti-rat CD154 monoclonal antibody, in a fully allogeneic acute(u) into Lewis [LEW] (RT11) and chronic [WF.1L (RT1l) into LEW (RT1l)] vascularized cardiac allograft rejection model. In the chronic model, the antibody was evaluated for prevention (starting day of transplant) and interruption of progression (starting day 30 or 60 after transplant) of chronic vasculopathy. Graft survival, morphology, and immunohistology were evaluated. RESULTS: In the acute rejection model, anti-CD154 therapy alone prevented acute allograft rejection and resulted in 50% long-term allograft survival (>200 days) and donor-specific tolerance. In recipients treated with anti-CD154 monoclonal antibody in combination with a short course of cyclosporine, 100% of allografts survived long-term and all recipients achieved donor-specific tolerance. In the chronic rejection model, allografts from animals treated with the anti-CD154 antibody had a statistically significant lower score of graft arteriosclerosis and fibrosis in both the prevention and 30-day interruption groups when compared with control allografts. In addition, immunohistochemistry showed a decrease in intragraft mononuclear cell infiltration and activation. CONCLUSION: A new anti-CD154 antibody not only prevents acute allograft rejection, but also inhibits and interrupts the development of chronic rejection. In the acute rejection model cyclosporine acts synergistically with anti-CD154 therapy to prolong allograft survival and induce tolerance. In the chronic rejection model relatively early initiation of therapy is essential to prevent progression of chronic allograft vasculopathy and fibrosis.

Mechanisms of targeting CD28 by a signaling monoclonal antibody in acute and chronic allograft rejection.

There is increasing evidence that ongoing T-cell recognition of alloantigen and activation are key mediators of chronic allograft rejection. The CD28-B7 pathway is unique among costimulatory pathways in that two alternate ligands for B7 exist: CD28 and CTLA4. Recently, it has been suggested that CTLA4 negative signaling may be required for induction of acquired tolerance in vivo. A strategy by which the T cell is targeted at the CD28 receptor rather than its ligands would theoretically allow the inhibitory functions of the CTLA4-B7-1/2 axis to remain intact. Using a rat-specific monoclonal antibody, we investigated the effect of targeting CD28 in a model of chronic rejection without the confounding variable of immunosuppression. We also used an acute cardiac allograft rejection model to investigate CD28 stimulation-based strategies to induce donor-specific tolerance. We demonstrated that anti-CD28 monoclonal antibody was as effective as CTLA4 immunoglobulin in protecting against chronic allograft vasculopathy. In addition, a short course of cyclosporine therapy synergized with either anti-CD28 monoclonal antibody or CTLA4 immunoglobulin, suggesting that it may be clinically relevant to combine low-dose calcineurin inhibitors with CTLA4 immunoglobulin or anti-B7 antibodies. Finally, we report on the potential mechanisms of action of targeting CD28 in vivo.

Anti-CD28 monoclonal antibody therapy prevents chronic rejection of renal allografts in rats.

The effects of a signaling anti-CD28 mAb (JJ319), which interferes with the CD28-B7 T cell costimulation pathway thought to be involved in the development of chronic rejection of organ transplants, was investigated. Functional, morphologic, and molecular changes in rat renal allografts were examined up to 24 wk after placement. Control Lewis rats, recipients of F344 kidneys, received a single dose of a nonspecific mouse mAb intravenously on the day of transplantation (group 1). Group 2 animals were given anti-CD28 mAb in similar fashion. Group 3 animals were treated with a short course of cyclosporin A (CsA), and group 4 received both anti-CD 28 mAb and CsA. The majority (>95%) of animals in groups 2, 3, and 4 survived throughout the follow-up, compared with 28% in group 1 (P < 0.001). Group 2 and 4 recipients produced negligible proteinuria, whereas group 1 controls developed progressively increasing proteinuria after 4 wk and group 3 animals developed proteinuria by 24 wk. Allografts in groups 2 and 4 were morphologically unremarkable at 24 wk. Kidneys of group 1 animals rapidly developed changes of acute rejection, and those that survived long-term showed extensive glomerulosclerosis and interstitial fibrosis. Changes of early chronic rejection were noted in group 3 grafts. By reverse transcriptase-PCR, expression of representative inflammatory factors interferon-gamma and interleukin-10 were significantly elevated at 24 wk only in the surviving group 1 animals. A single dose of a signaling anti-CD28 mAb administered at transplantation or in combination with a short course of CsA significantly prolonged recipient survival, normalized function, and preserved the morphology of renal allografts in an established model of chronic rejection. These data support an important role for T cell costimulation in the evolution of the chronic process.