DELAYED TYPE HYPERSENSITIVITY (DTH) AND CRESCENTIC GLOMERULONEPHRITIS (GN) REQUIRE GM‐CSF, WHEREAS NEUTROPHIL MEDIATED GLOMERULAR INJURY REQUIRES BOTH G‐CSF AND GM‐CSF

ABSTRACT. Proliferative glomerulonephritis in humans is characterized by the presence of leukocytes in glomeruli. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) can potentially stimulate or affect T cell, macrophage, and neutrophil function. To define the roles of GM-CSF and G-CSF in leukocyte-mediated glomerulonephritis, glomerular injury was studied in mice genetically deficient in either GM-CSF (GM-CSF −/− mice) or G-CSF (G-CSF −/− mice). Two models of glomerulonephritis were studied: neutrophil-mediated heterologous-phase anti-glomerular basement membrane (GBM) glomerulonephritis and T cell/macrophage-mediated crescentic autologous-phase anti-GBM glomerulonephritis. Both GM-CSF −/− and G-CSF −/− mice were protected from heterologous-phase anti-GBM glomerulonephritis compared with genetically normal (CSF WT) mice, with reduced proteinuria and glomerular neutrophil numbers. However, only GM-CSF −/− mice were protected from crescentic glomerular injury in the autologous phase, whereas G-CSF −/− mice were not protected and in fact had increased numbers of T cells in glomeruli. Humoral responses to the nephritogenic antigen were unaltered by deficiency of either GM-CSF or G-CSF, but glomerular T cell and macrophage numbers, as well as dermal delayed-type hypersensitivity to the nephritogenic antigen, were reduced in GM-CSF −/− mice. These studies demonstrate that endogenous GM-CSF plays a role in experimental glomerulonephritis in both the autologous and heterologous phases of injury.

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INTRINSIC RENAL CELL DERIVED IL‐12 IS AN EFFECTOR OF RENAL GLOMERULAR INJURY IN CRESCENTIC GLOMERULONEPHRITIS

Nephrology ◽

10.1046/j.1440-1797.2000.abs127.x ◽

2000 ◽

Vol 5 (3) ◽

pp. A98-A98

Author(s):

Timoshanko Jr ◽

Kitching Ar ◽

Holdsworth Sr ◽

Tipping PG.

Keyword(s):

Renal Cell ◽

Crescentic Glomerulonephritis ◽

Glomerular Injury

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Case Report: Patient with Hepatitis C, p-ANCA, and Cryoglobulin Antibodies Presenting with Necrotizing Crescentic p-ANCA Glomerulonephritis

Case Reports in Nephrology and Dialysis ◽

10.1159/000491629 ◽

2018 ◽

Vol 8 (2) ◽

pp. 161-170

Author(s):

Ramy M. Hanna ◽

Naomi So ◽

Marian Kaldas ◽

Jean Hou ◽

Farid Arman ◽

...

Keyword(s):

Hepatitis C ◽

Crescentic Glomerulonephritis ◽

The United States ◽

Cross Reactivity ◽

Normal Serum ◽

Hcv Infection ◽

Low Grade ◽

Glomerular Injury ◽

Immune Assays

Hepatitis C (HCV) infection has a prevalence of 3 million infected individuals in the United States, according to recent Center for Disease Control reports, and can have various renal manifestations. Cryoglobulins, antibodies that precipitate at colder temperatures in vitro, are a relatively common cause of renal disease in HCV infection. The cryoglobulin proteins can form occlusive aggregates in small glomerular capillary lumina or deposit in other areas of the glomerulus, resulting in hypocomplementemia, proteinuria, hematuria, and renal injury. The typical biopsy pattern is that of membranoproliferative glomerulonephritis (MPGN). There are, however, other HCV-related patterns of glomerular injury. Anti-neutrophil cytoplasmic antibodies (ANCA) are known to exist in HCV-infected patients. In many reported cases, ANCA serologic testing may appear positive due to cross-reactivity of the immune assays; however, the biopsy findings do not support ANCA-associated crescentic glomerulonephritis (GN)/vasculitis as the primary cause of glomerular injury. There are rare reports of microscopic polyangiitis (MPA) p-ANCA vasculitis, in patients with HCV infection. In comparison with the MPGN pattern of cryoglobulinemic glomerular injury, biopsies from these HCV-infected patients with concomitant MPA revealed a crescentic GN, associated with normal serum complement levels. We present a case of HCV-associated glomerular disease with the surprising biopsy finding of necrotizing and crescentic p-ANCA GN, with a background, low-grade mesangial immune complex GN. Thus, p-ANCA disease should also be considered in HCV-infected patients, in addition to the more typical lesions of MPGN or cryoglobulinemic GN.

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Crescentic glomerulonephritis associated with prostatic carcinoma: Evidence of immune-mediated glomerular injury

The American Journal of Medicine ◽

10.1016/0002-9343(90)90473-q ◽

1990 ◽

Vol 88 (2) ◽

pp. 189-192 ◽

Cited By ~ 8

Author(s):

Lloyd P. Haskell ◽

Mary Jean Fusco ◽

Scott Wadler ◽

Leonarda B. Sablay ◽

Ralph P. Mennemeyer

Keyword(s):

Prostatic Carcinoma ◽

Crescentic Glomerulonephritis ◽

Glomerular Injury ◽

Immune Mediated

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Posttransplant Immunotherapy with a GM-CSF-Based Tumor Vaccine (GVAX®) Following Autologous Stem Cell Transplant (ASCT) for Acute Myeloid Leukemia (AML).

Blood ◽

10.1182/blood.v104.11.441.441 ◽

2004 ◽

Vol 104 (11) ◽

pp. 441-441

Author(s):

Daniel J. DeAngelo ◽

Edwin P. Alyea ◽

Ivan M. Borrello ◽

Hyam I. Levitsky ◽

Wendy Stock ◽

...

Keyword(s):

Bone Marrow ◽

Stem Cell ◽

Leukemia Cell ◽

Delayed Type Hypersensitivity ◽

Leukemia Cells ◽

Autologous Tumor ◽

Cell Transplant ◽

Vaccine Platform ◽

Blood Draw ◽

Gm Csf

Abstract Background: Preclinical models have demonstrated the efficacy of GM-CSF secreting cancer vaccines accompanied by vaccine-primed lymphocyte infusion following ASCT. Methods: Patients ≤ 60 years old with de novo AML (excluding M3) were enrolled. Leukemia cells were harvested at diagnosis followed by induction and consolidation chemotherapy and ASCT. A pretransplant vaccine composed of irradiated autologous leukemia cells mixed with GM-CSF gene-modified K562 cells (CG9962) was given followed by collection of vaccine-primed lymphocytes that were reinfused with the stem cell graft. Posttransplant vaccinations were initiated at week 6 (or upon platelet engraftment) and given every 3 weeks (10x107 tumor cells + 4x107 CG9962 cells) x 8 vaccinations. Results: Leukemia cell harvest was successful in 51/54 patients (blood draw − 22, leukapheresis − 28, bone marrow aspirate − 4). To date, 44/54 patients (81%) have achieved a complete remission (CR) following induction chemotherapy, 27 have received the pretransplant vaccination, and 15 have initiated posttransplant vaccinations. Local vaccine injection site reactions developed in all patients. Delayed-type hypersensitivity (DTH) reactions to irradiated, autologous tumor were induced post vaccination in 4/11. Antibodies reactive against autologous tumor were induced in 5/11 and against CG9962 cells in 10/10. Minimal residual disease (MRD) is being monitored by quantitative analysis of peripheral blood (PB) and bone marrow (BM) for WT1, a leukemia-associated gene, by RT-PCR. All patients had detectable WT1 transcripts in PB and BM at diagnosis. Most patients in CR had persistently detectable WT1 transcripts in BM following induction (92%), consolidation (91%), and ASCT (63%), whereas, clearance of WT-1 in PB was more frequent (49% detectable post induction, 50% post consolidation, and 31% post ASCT). A decrease in WT1 was noted in 67% (12/18 in the BM and 10/15 in PB) following the pretransplant vaccination. Conclusions: Collection of large quantities of autologous leukemia cells for vaccine production is feasible. Reduction in WT-1 transcript levels following the pre-transplant vaccine suggests anti-leukemic activity of this GVAX® vaccine platform.

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Vaccination with Lymphoma and Dendritic Cell Hybrids Intended as an Adjuvant Therapy for Lymphoma Patients - A Feasibility Study.

Blood ◽

10.1182/blood.v108.11.5187.5187 ◽

2006 ◽

Vol 108 (11) ◽

pp. 5187-5187

Author(s):

Sergiusz Markowicz ◽

Anna Jakubowska-Mucka ◽

Marzena Biernacka ◽

Grzegorz Rymkiewicz ◽

Anna Borawska ◽

...

Keyword(s):

Bone Marrow ◽

Dendritic Cell ◽

Delayed Type Hypersensitivity ◽

Adherent Cells ◽

Tumor Lysate ◽

Lymphoma Cells ◽

Representative Case ◽

Gm Csf ◽

Cell Hybrids ◽

Disease Free

Abstract A feasibility of hybrid cell vaccination performed in remission following a standard chemotherapy (CHT) is currently being studied in patients with indolent B cell lymphomas at our institution under approval of the Ethics Committee. Adequate samples of fresh tumor tissue were collected from 16 patients. Seven patients were vaccinated with irradiated lymphoma/dendritic cell (DC) hybrids, and whenever the amount of collected viable lymphoma cells was not sufficient to complete vaccination with the use of cell hybrids, booster injections were alternatively performed with the use autologous DCs pulsed with tumor lysate. Autologous lymphoma cells were electrofused with autologous and/or allogeneic DCs, depending on accessibility of autologous DCs. Monocyte-derived DCs were basically generated from the peripheral blood adherent cells stimulated with GM-CSF and IL-4, and if available, from the bone marrow (BM) adherent cells. If only possible, autologous DCs were also generated from the BM non-adherent cells or from a sample of leukapheresis product collected for transplantation cultured with GM-CSF, TNF-α, SCF and FLT3-L to induce differentiation of DC progenitors. DC hybrids and/or DCs preincubated with tumor lysate were administered to uninvolved lymph nodes under USG guidance. Four patients failed to achieve a complete remission after initial therapy and the vaccination was discontinued due to disease progression (after 2, 2, 6, and 5 cycles). Three patients were vaccinated during remission following CHT. At present - 16, 18, and 10 months after starting the immunization, and after 8, 9, and after 7 cycles of vaccination, one patient with mantle cell lymphoma (MCL) is symptomless with persistent bone marrow (BM) involvement, one patient with MCL presenting with IgM paraproteinemia is disease-free with residual BM involvement (Fig 1), and one patient with follicular lymphoma is disease-free. Cutaneous delayed type hypersensitivity (DTH) response to DC/lymphoma hybrids exceeded the response to DCs alone in 3 of 7 vaccinated patients, and interferon-γ producing CD8+ cells specific to autologous lymphoma cells were demonstrated in one patient. In another patient, cutaneous DTH reaction was accompanied by transient pruritus and swelling of the injected lymph node two days after the sixth booster injection. No other adverse reactions to vaccinations were observed. Vaccination using the DC/lymphoma hybrids appears feasible, safe, and capable of inducing lymphoma cell specific immune responses. Further evaluation of efficacy in terms of disease control is mandatory. Fig 1. Disease and treatment course of a representative case Fig 1. Disease and treatment course of a representative case

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Idiotype Vaccination in Human Myeloma: Generation of Tumor-Specific Immune Responses After High-Dose Chemotherapy

Blood ◽

10.1182/blood.v94.2.673 ◽

1999 ◽

Vol 94 (2) ◽

pp. 673-683 ◽

Cited By ~ 109

Author(s):

Massimo Massaia ◽

Paolo Borrione ◽

Silvano Battaglio ◽

Sara Mariani ◽

Eloise Beggiato ◽

...

Keyword(s):

Immune Responses ◽

Residual Disease ◽

Interleukin 2 ◽

Keyhole Limpet Hemocyanin ◽

High Dose Chemotherapy ◽

Outpatient Setting ◽

Delayed Type Hypersensitivity ◽

High Dose ◽

Gm Csf ◽

Macrophage Colony

Abstract Igs contain unique portions, collectively termed idiotypes (Id), that can be recognized by the immune system. Id expressed by tumor cells in B-cell malignancies can be regarded as tumor-specific antigens and a target for vaccine immunotherapy. We have started a vaccination trial in multiple myeloma (MM) using Id-specific proteins conjugated to keyhole limpet hemocyanin (KLH) as immunogens and low doses of subcutaneous granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-2 (IL-2) as immunoadjuvants. Twelve patients who had previously been treated with high-dose chemotherapy followed by peripheral blood progenitor cell (PBPC) transplantation entered this study from August 1995 to January 1998. All patients were in first remission at the time of vaccination. They received subcutaneous injections of Id vaccines and immunoadjuvants in an outpatient setting. The generation of Id-specific T-cell proliferative responses was documented in 2 patients, whereas a positive Id-specific delayed-type hypersensitivity (DTH) reaction was observed in 8 of the 10 patients studied. DTH specificity was confirmed in 1 patient by investigating the reactivity to synthetic peptides derived from the VDJ sequence of the tumor-specific Ig heavy chain. None of the patients generated soluble immune responses to Id, whereas the generation of soluble and cellular immune responses to KLH was observed in 100% and 80%, respectively. Eleven patients completed the treatment, whereas 1 patient failed to finish owing to progression of disease. Freedom from disease progression (FFDP), measured from the date of first Id/KLH injection to the date of first treatment after vaccination or last follow-up, ranged from 9 to 36 months. These data indicate that the immune competence status of MM patients is still susceptible to specific immunization after high-dose chemotherapy and PBPC transplantation. It remains to be determined whether generation of Id-specific immune responses can reduce the relapse rate of patients with minimal residual disease.

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Risk factors for development of delayed urticarial reactions in the phase II trial of HER2 peptide vaccines plus GM-CSF versus GM-CSF alone in high-risk breast cancer patients to prevent recurrence.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.3097 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 3097-3097

Author(s):

Alfred F Trappey ◽

John S. Berry ◽

Timothy J Vreeland ◽

Diane F. Hale ◽

Alan K. Sears ◽

...

Keyword(s):

Breast Cancer ◽

Risk Factors ◽

Immune Response ◽

High Risk ◽

Phase Ii ◽

Phase Ii Trial ◽

Delayed Type Hypersensitivity ◽

Breast Cancer Patients ◽

Duration Of Symptoms ◽

Gm Csf

3097 Background: We are monitoring the incidence of delayed urticarial reactions (DURs) in our phase II trial evaluating adjuvant HER2-specific vaccines (AE37 and GP2) for the prevention of breast cancer recurrence. Here, we characterize DURs and analyze risk factors for their development. Methods: After completion of standard of care therapy, disease-free node-positive or high-risk node-negative patients (pts) were randomized to receive either a peptide+GM-CSF (VG) or GM-CSF (CG). Pts receive 6 monthly intradermal inoculations during the primary vaccine series (PVS) then four boosters (B) every 6 mos. Immune response is measured by delayed type hypersensitivity (DTH) pre- (R0) and post-PVS (R6) and local reaction (LR) at R1 – R6. Results: Twenty-four (6.1%) of 393 initiated patients report a DUR; 13 VG (vDUR), and 11 CG (cDUR); vDUR - 9 AE37, 4 GP2. Time to onset of symptoms is 9±5 days (d) and is similar in vDUR/cDUR (p = 0.27). DURs manifest as hives/pruritis in all patients. Average duration of symptoms is 32.6 d ± 8.8 d (no difference in vDUR/cDUR [p = 0.23]). Episodes have resolved with antihistamines or IV/oral steroids. Ten (4 cDUR, 6 vDUR) patients have had recurrent episodes that have resolved similarly. 75% of first episodes occur between R6-B3. For DUR patients v. those who have not had a DUR (noDUR), there are no differences in demographics. DTH response is similar in vDUR pts v. noDUR VG pts (R0- p = 0.34; R6- p=0.40). cDUR pts had a greater DTH response v. CG noDUR pts at R6 (13.2 v 4.7 mm, p=0.01). LRs are greater in DUR pts compared to noDUR pts after the second vaccination (R2 – 66.2 v 48.2 mm, p=0.02). LR for DUR pts decrease and are less than noDUR at R6 (45.4 v 57.4 mm, p=0.09). Relative risk for developing DUR for LR > 100 mm at R2 is 3.49 (1.58-7.68, 95% CI [p=0.004]). At 29.9 months median follow-up, there have been no recurrences in VG and CG DUR v. 75.9% DFS for noDUR (p=0.05). Conclusions: DURs occur infrequently and without long-term sequelae. Pts at risk for developing DUR are identified early in the vaccine series using LR. Robust immune response in DUR may explain the survival benefit demonstrated here. Clinical trial information: NCT00524277.

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A phase I/II trial of TG01/GM-CSF and gemcitabine as adjuvant therapy for treating patients with resected RAS-mutant adenocarcinoma of the pancreas.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.4119 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 4119-4119 ◽

Cited By ~ 7

Author(s):

Daniel H. Palmer ◽

Svein Dueland ◽

Juan W. Valle ◽

Anne-Kirsti Aksnes

Keyword(s):

Pancreatic Cancer ◽

T Cell ◽

Immunological Response ◽

Intradermal Injection ◽

Delayed Type Hypersensitivity ◽

Allergic Reactions ◽

Kras Mutations ◽

Gm Csf ◽

Cell Responses ◽

Adenocarcinoma Of The Pancreas

4119 Background: TG01 (a mixture of 7 RAS peptides) is an injectable antigen-specific cancer immunotherapy targeted to treat patients (Pts) with KRAS mutations, found in more than 85% of pancreatic adenocarcinomas. There is scope for improvement in adjuvant treatment of resected pancreatic cancer; with 1- and 2-year published overall survival (OS) rates ranging from 56-80% and 30-54% respectively. TG01 induces RAS mutant-specific T-cell responses which are enhanced by co-administration of GM-CSF. This study evaluates safety, immunological response and OS of TG01-immunotherapy with adjuvant gemcitabine chemotherapy. Methods: Pts were eligible after an R0 or R1 pancreatic adenocarcinoma resection. As soon as possible after surgery, TG01 (0.7 mg intradermal injection (id)) together with GM-CSF (0.03 mg id) was given on days 1, 3, 5, 8, 15, 22 and 2-weekly thereafter until the end of gemcitabine (starting within 12 weeks of surgery and given for 6 cycles). Thereafter TG01/GM-CFS were given 4-weekly up to 1 yr and 12-weekly up to 2 yrs. Immune response was assessed using antigen-specific (TG01) Delayed-Type Hypersensitivity (DTH) and T-cell proliferation. OS was assessed from surgery; ~8 weeks before first TG01 injection. Results: To date, 19 pts (68% R1) from 3 sites (Norway and UK) and have been followed for 2 yrs.Eight SARs in 5 pts have occurred; 4 related to gemcitabine (anemia, pulmonary infection and 2 fever); 3 related to TG01/GM-CSF (2 anaphylaxes and 1 hypersensitivity); and 1 possibly related to all products (dyspnea). The allergic reactions only occurred after several cycles of gemcitabine and resolved within 1-2 hrs. There was no treatment related deaths.16/19 (84%) pts had a positive DTH by week 11. Proliferation of mutant RAS specific T-cells is being analyzed. OS rate at 1 and 2 yrs were 89.5% (95% CI 75.7, 100.0) and 68.4 (95% CI 47.5, 89.3), respectively. Median OS was 33.1 months (95% CI 16.8, 40.1). Conclusions: TG01/GM-CSF generated early immune responses in 84% of patients with R0/R1 resected pancreatic cancer. The regimen was generally well tolerated although some late, manageable allergic reactions were seen. OS was encouraging in view of published reports. Clinical trial information: NCT02261714.

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IL-18 Has IL-12-Independent Effects in Delayed-Type Hypersensitivity: Studies in Cell-Mediated Crescentic Glomerulonephritis

The Journal of Immunology ◽

10.4049/jimmunol.165.8.4649 ◽

2000 ◽

Vol 165 (8) ◽

pp. 4649-4657 ◽

Cited By ~ 35

Author(s):

A. Richard Kitching ◽

Peter G. Tipping ◽

Masashi Kurimoto ◽

Stephen R. Holdsworth

Keyword(s):

Crescentic Glomerulonephritis ◽

Delayed Type Hypersensitivity ◽

Independent Effects

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