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Biomedical subjects

Herman Waldmann

Publications and source records attributed to Herman Waldmann.

62 records · Page 4Linked to original sources
PubMed2002

Limiting transplantation-related mortality following unrelated donor stem cell transplantation by using a nonmyeloablative conditioning regimen.

A nonmyeloablative conditioning regimen was investigated in 47 patients with hematological malignancy receiving allogeneic progenitor cells from matched, unrelated donors. The median patient age was 44 years. The majority of patients had high-risk features, including having failed a prior transplantation (29 individuals). Twenty of the transplants were mismatched for HLA class I and/or class II alleles. Recipient conditioning consisted of 20 mg CAMPATH-1H on days -8 to -4, 30 mg/m(2) fludarabine on days -7 to -3, and 140 mg/m(2) melphalan on day -2. Graft-versus-host disease (GVHD) prophylaxis was with cyclosporine A alone. Primary graft failure occurred in only 2 of 44 evaluable patients (4.5%). Chimerism studies in 34 patients indicated that the majority (85.3%) attained initial full donor chimerism. Only 3 patients developed grade III to IV acute GVHD, and no patients have yet developed chronic extensive GVHD. The estimated probability of nonrelapse mortality at day 100 was 14.9% (95% confidence interval [CI], 4.7%-25.1%). With a median follow-up of 344 days (range, 79-830), overall and progression-free survivals at 1 year were 75.5% (95% CI, 62.8%-88.2%) and 61.5% (95% CI, 46.1%-76.8%), respectively. In summary, a nonmyeloablative regimen incorporating in vivo CAMPATH-1H is effective in promoting durable engraftment in most patients and in reducing the risk of severe GVHD following matched unrelated donor transplantation.

Adolescent↗
PubMed2002

Regulatory T cells overexpress a subset of Th2 gene transcripts.

There is now compelling evidence for subpopulations of CD4+ T cells whose role is to prevent immune pathology in both autoimmunity and transplantation. We have cloned CD4+ T cells against a male transplantation Ag that, unlike Th1 or Th2 clones, suppresses the rejection of male skin grafts and are therefore considered examples of regulatory T cells. We have identified, using serial analysis of gene expression, transcripts that are overexpressed in regulatory T cells compared with Th1 and Th2 clones. Some of these transcripts are increased in tolerated rather than rejecting skin grafts and in addition are expressed by the natural regulatory CD4+CD25+ subpopulation of naive mice. These genes include prepro-enkephalin, GM2 ganglioside activator protein, glucocorticoid-induced TNFR superfamily member 18, and integrin alpha(E)beta(7). They seem to represent a subset of transcripts shared with Th2 cells, suggesting that transplantation tolerance and normal immunoregulation may represent a unique form of Th2-like differentiation.

Adoptive Transfer↗
PubMed2002

Reprogramming the immune system.

The immune system is organized so as to react to pathogens without risking damage to self. Harnessing those processes that prevent self-reactivity will have enormous potential in clinical medicine. This review outlines the efforts of this laboratory over the last 25 years to exploit tolerance so as to reprogram the immune system for therapeutic purposes.

Allergy and Immunology↗
PubMed2002

The vaccinia virus C12L protein inhibits mouse IL-18 and promotes virus virulence in the murine intranasal model.

A bioassay that measured the interleukin (IL)-12-induced production of interferon (IFN)-gamma from mouse splenocytes was used to identify a soluble factor in the supernatants of vaccinia virus (VV)-infected cells that inhibited the production of IFN-gamma. This soluble factor was expressed by 14 out of 16 VV strains including the Western Reserve (WR) strain, but strains Copenhagen and Tashkent and a mutant of strain WR called 6/2 lacked this activity. The gene encoding this activity was identified as C12L by transferring DNA present in VV WR but missing in VV WR 6/2 into VV Copenhagen and testing for expression of the soluble factor. The C12L protein shows amino acid similarity to IL-18 binding proteins that are encoded by poxviruses, mice and humans, and C12L protein produced from VV or baculovirus inhibited the biological activity of mouse IL-18 in vitro. Thus the inhibition of IL-12-induced IFN-gamma production was due to indirect effects of C12L on IL-18, illustrating the synergistic action of these pro-inflammatory cytokines. To study the role of the C12L protein in the virus life-cycle, we constructed a deletion mutant lacking the C12L gene and a revertant virus in which the gene was reinserted into the deletion mutant. In vitro the replication and plaque size of these viruses were indistinguishable. However, infection of BALB/c mice by the intranasal route showed that the deletion mutant was attenuated and induced lower weight loss and signs of illness compared to controls.

Administration, Intranasal↗
PubMed2002

A personal history of the CAMPATH-1H antibody.

The recent licensing of CAMPATH-1H (alemtuzumab) for the treatment of patients with refractory chronic lymphocytic leukemia has been the culmination of a long journey. This success is in large part due to the persistence, dedication, and commitment of a large number of academic collaborators. The first breakthrough was the identification of CAMPATH-1M, an isotype directed against CD52, and extremely efficient at lysing target cells in the presence of human complement, but limited in vivo by the rate of complement biosynthesis. The search for a monoclonal antibody that was more efficient in vivo found the rare class-switching variant CAMPATH-1G, which is able to kill target cells by antibody-dependent cell-mediated cytotoxicity. Construction of the humanized form of the antibody, CAMPATH-1H, and the development of resources to manufacture clinical-grade material, further expedited many studies across the world in leukemia and lymphoma as well as in marrow transplantation, autoimmune disorders, and kidney transplantation. Such studies have taught us a lot about the diseases themselves, as well as offering the prospect of harnessing immunological tolerance processes to facilitate a whole new approach to immunosuppression.

Alemtuzumab↗
PubMed2001

The role of Sp1 and NF-kappa B in regulating CD40 gene expression.

CD40 is a member of the tumor necrosis factor receptor superfamily and is a key signaling molecule expressed by antigen-presenting cells of the immune system. In a previous paper, we demonstrated that the expression of CD40 is regulated by both post-transcriptional and post-translational processes. In this paper, we show that basal (constitutive) CD40 gene expression is regulated by a TATA-less promoter, with Sp1 as a key transcription factor. Two Sp1 binding regions were identified in the mouse CD40 promoter at positions -59 to -50 and -74 to -66. Surprisingly, Sp1-mediated CD40 transcription was reduced following lipopolysaccharide stimulation and was associated with a time-dependent reduction in Sp1 DNA binding activity. This reduction seemed to be mediated by phosphorylation of the Sp1 molecule. We also show here that CD40 expression in lipopolysaccharide-stimulated cells is up-regulated by NF-kappaB through two distinct sites. One of these sites (-128 to -119) was shown to bind p50 and p65 members of the NF-kappaB family, while the other site (-562 to -553) bound only p65. Transfectants of p65 were generated using RAW 264 cells, and it was shown that the up-regulation of CD40 mRNA expression was dependent on the presence of the p65 molecule.

Base Sequence↗
PubMedDate not supplied

Clinical evidence of a graft-versus-Hodgkin's-lymphoma effect after reduced-intensity allogeneic transplantation.

BACKGROUND: In patients with multiply relapsed Hodgkin's lymphoma allogeneic stem-cell transplantation has been limited by prohibitive non-relapse-related mortality rates and by a lack of definitive evidence for a therapeutic graft-versus-tumour effect. Therefore, we aimed to assess the graft-versus-tumour effect of reduced-intensity allogeneic transplantation. METHODS: We undertook reduced-intensity transplantation in 49 patients with multiply relapsed Hodgkin's lymphoma, 44 (90%) of whom had progression of disease after previous autologous transplantation (median age 32 years [range 18-51], number of previous treatment courses was five [range 3-8], and time from diagnosis 4.8 years [range 0.6-4.8]). 31 patients had HLA matched donors who were related and 18 had donors who were unrelated. Median follow-up was 967 days (range 102-2232). The primary endpoints were engraftment, toxic effects, non-relapse-related mortality, incidence of graft-versus-host disease (GVHD), and the toxic effects of adjuvant donor-lymphocyte infusion. FINDINGS: All patients engrafted. Eight of 49 (16%) had grade II-IV acute GVHD and seven (14%) had chronic GVHD before donor-lymphocyte infusion. 16 (33%) patients received donor-lymphocyte infusion from 3 months after transplantation for residual disease or progression. Six (38%) of the 16 developed grade II-IV acute GVHD and five developed chronic GVHD. Nine (56%) showed disease responses after infusion (eight complete, one partial). Non-relapse-related mortality was 16.3% at 730 days (7.2% for patients who had related donors vs 34.1% for those with unrelated donors, p=0.0206). Projected 4 year overall and progression-free survival were 55.7% and 39.0%, respectively (62.0% and 41.5% for related donors). INTERPRETATION: These data show the potential for durable responses in patients who have previously had substantial treatment for Hodgkin's lymphoma. The low non-relapse-related mortality suggests the procedure could be undertaken earlier in the course of the disease.

Adolescent↗