Update on HIV lymphoma

In industrialized nations people infected with HIV remain at increased risk for malignancies despite highly active antiretroviral therapy. In these countries, lymphoma is the most common HIV-associated malignancy. This review summarizes progress from January 2005 to February 2007. The majority of investigation has been in diffuse large B cell lymphoma, with infusional therapy remaining promising but cumbersome. Rituximab likely improves complete response rates, and, possibly overall survival, but is likely associated with increased infections in a subset of patients with very low CD4 counts. Biologic insights have been attained in the spectrum of HIV-associated non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, and virologic coinfections. Overall, the outcome for non-Hodgkin’s lymphoma and Hodgkin’s lymphoma in the setting of HIV continues to improve as insights into the pathophysiology and treatment advance.     

DnIKK2-transfected dendritic cells induce a novel population of inducible nitric oxide synthase-expressing CD4+CD25- cells with tolerogenic properties

BACKGROUND: We previously documented that rat bone marrow-derived dendritic cells (DCs), transfected with an adenovirus encoding a dominant negative form of IKK2 (dnIKK2), have impaired allostimulatory capacity and generate CD4 T cells with regulatory function. Here we investigate the potency, the phenotype, and the mechanism of action of dnIKK2-DC-induced regulatory cells and we evaluated their tolerogenic properties in vivo. METHODS: Brown Norway (BN) transfected dnIKK2-DCs were cultured with Lewis (LW) lymphocytes in primary mixed lymphocyte reaction (MLR). CD4 T cells were purified from primary MLR and incubated in secondary coculture MLR with LW lymphocytes. Phenotypic characterization was performed by fluorescence-activated cell sorting and real-time polymerase chain reaction. The tolerogenic potential of CD4 T cells pre-exposed to dnIKK2-DCs was evaluated in vivo in a model of kidney allotransplantation. RESULTS: CD4 T cells pre-exposed to dnIKK2-DCs were CD4CD25 and expressed interleukin (IL)-10, transforming growth factor-beta, interferon-gamma, IL-2, and inducible nitric oxide synthase (iNOS). These cells (dnIKK2-Treg), cocultured (at up to 1:10 ratio) with a primary MLR, suppressed T-cell proliferation to alloantigens. The regulatory effect was cell-to-cell contact-independent since it was also observed in a transwell system. A nitric oxide synthase inhibitor significantly reverted dnIKK2-Treg-mediated suppression, whereas neutralizing antibodies to IL-10 and TGF-beta had no significant effect. DnIKK2-Treg given in vivo to LW rats prolonged the survival of a kidney allograft from BN rats (the donor rat strain used for generating DCs). CONCLUSIONS: DnIKK2-Treg is a unique population of CD4CD25 T cells expressing high levels of iNOS. These cells potently inhibit T-cell response in vitro and induce prolongation of kidney allograft survival in vivo.     

Response-adapted therapy with infusional EPOCH chemotherapy plus rituximab in human immunodeficiency virus-associated,B-cell non-Hodgkin lymphoma

Four cycles of rituximab plus CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy is as effective as six cycles in low-risk diffuse large B-cell lymphoma (DLBCL). Here we report a post-hoc analysis of a prospective clinical trial in patients with human immunodeficiency virus-associated DLBCL and high-grade lymphoma treated with four to six cycles of EPOCH plus rituximab based on a response-adapted treatment strategy. One hundred and six evaluable patients with human immunodeficiency virus-associated DLBCL or highgrade CD20⁺ non-Hodgkin lymphoma were randomized to receive rituximab (375 mg/m2) given either concurrently prior to each infusional EPOCH cycle, or sequentially (weekly for 6 weeks) following completion of EPOCH. EPOCH consisted of a 96-hour intravenous infusion of etoposide, doxorubicin, and vincristine plus oral prednisone followed by an intravenous bolus of cyclophosphamide every 21 days for four to six cycles. Patients received two additional cycles of therapy after documentation of a complete response by computed tomography after cycles 2 and 4. Sixty-four of 106 evaluable patients (60%; 95% confidence interval [95% CI]: 50%-70%) in both treatment arms had a complete response. The 2-year event-free survival rates were similar in the 24 patients with complete response who received four or fewer cycles of EPOCH (78%; 95% CI: 55%-90%) due to having achieved a complete response after two cycles, compared with those who received five or six cycles of EPOCH (85%; 95% CI: 70%-93%) because a complete response was first documented after cycle 4. A response-adapted strategy may permit a shorter treatment duration without compromising therapeutic efficacy in patients with human immunodeficiency virus-associated lymphoma treated with EPOCH plus rituximab, which merits further evaluation in additional prospective trials. Clinical Trials.gov identifier {"type":"clinical-trial","attrs":{"text":"NCT00049036","term_id":"NCT00049036"}}NCT00049036.     

SYMPOSIUM Experimental Biology 1995 Endothelin Receptors: Role in Renal Function and Dysfunction ENDOTHELIN IS A KEY MODULATOR OF PROGRESSIVE RENAL INJURY: EXPERIMENTAL DATA AND NOVEL THERAPEUTIC STRATEGIES

1. Glomerulosclerosis and tubulointerstitial damage are common histological abnormalities of many renal diseases that progress to end-stage renal failure.
2. In some models of renal damage, glomerulosclerosis seems to be associated with increased glomerular capillary pressure.
3. Due to the positive correlation of glomerulosclerosis and proteinuria in both experimental models and in humans, abnormal permeability to macromolecules has also been considered a possible determinant of glomerulosclerosis.
4. Abnormally filtered macromolecules have an intrinsic toxicity to the kidney due to protein over-reabsorption, possibly leading to tubulointerstitial damage.
5. Endothelin-1 (ET-1) is a vasoconstrictor peptide that induces mitogenesis and the accumulation of matrix proteins by mesangial cells.
6. Evidence is available that ET-1 plays a role in progressive renal disease in different experimental models, including renal mass reduction, lupus nephritis, streptozotocin-induced diabetes and puromycin-induced nephrosis.