A polyvalent vaccine for high-risk prostate patients: “are more antigens better?”

We have shown the immunogenicity and safety of synthetic carbohydrate vaccines when conjugated to the carrier keyhole limpet hemocyanin (KLH) and given with the adjuvant, QS-21, in patients with biochemically relapsed prostate cancer. To determine whether immune response could be further enhanced with stimulation by multiple antigens, a hexavalent vaccine was prepared using previously determined doses and administered in a Phase II setting to 30 high-risk patients. The hexavalent vaccine included GM2, Globo H, Lewis^y, glycosylated MUC-1-32mer and Tn and TF in a clustered formation, conjugated to KLH and mixed with QS-21. Eight vaccinations were administered over 13 months. All 30 patients had significant elevations in antibody titers to at least two of the six antigens; 22 patients had increased reactivity with FACS. These serologic responses were lower than that seen previously in patients treated with the respective monovalent vaccines. The reciprocal median combined IgM and IgG antibody titers with ELISA against MUC1, Tn, TF, globo H and GM2 for these 30 patients were 640, 80, 120, 40 and 0, compared to 1280, 640, 1280, 320 and 160 seen in patients receiving individual monovalent vaccines. This hexavalent vaccine of synthetic “self” antigens broke immunologic tolerance against two or more antigens in all 30 vaccinated patients, was safe, but antibody titers against several of the antigens were lower than those seen in individual monovalent trials. No impact on PSA slope was detected. We address the relevance of the multivalent approach for prostate cancer treatment. Supported by the Prostate Cancer Foundation, The PepsiCo Foundation, The Sharon Hels and Brad Reed Fund, Swim Across America, The Sara Chait Foundation. Dr. Philip Livingston is a consultant for and shareholder in Progenics Pharmaceuticals, Inc.     

AIDS: A problem of antigen presentation?

Evidence is accumulating that antigen-presenting dendritic cells — both those that activate T cells and those that interact with B cells — may be involved in the development of immunodeficiency during HIV-1 infection.     

A “new” low incidence red cell antigen,NFLD

Summary A new low incidence red cell antigen, NFLD, is described. It was found in a Caucasian family and is inherited as an autosomal dominant. The antigen is not part of the AB0, MNSs, Duffy, Kidd, or Yt blood group systems and probably does not belong to the Rh or Kell blood group systems.     

Can the surface immobilization antigens of Philasterides dicentrarchi (Ciliophora: Scuticociliatida) be used as target antigens to develop vaccines in cultured fish?

In order to test whether immobilization antigens (i-antigens) of Philasterides dicentrarchi could be suitable antigenic targets against scuticociliatosis, polyclonal olive flounder (Paralichthys olivaceus) sera were raised against P. dicentrarchi by immunization with lysates of ciliates grown using chinook salmon epithelial (CHSE) cells, and the ability of the immune sera to kill the ciliates via classical complement pathway was analyzed in relation to agglutination activity. The immune sera showed clear agglutination activity against the CHSE-cultured ciliates. However, the agglutinated ciliates were not killed but escaped from the agglutinated mass within a few hours. Ciliates isolated from fish artificially infected with the same population of CHSE-cultured ciliates were not agglutinated by the immune sera even at the lowest dilution. In antibody-dependent complement-mediated killing (ADCK), the immune sera completely killed the CHSE-cultured ciliates at relatively higher serum dilutions (showing low or no agglutination activity). However, CHSE-cultured ciliates were not killed completely at lower immune serum dilutions (showing high agglutination activity). In contrast to CHSE-cultured ciliates, the ciliates isolated from infected fish were killed at lower dilutions of the immune sera in spite of no agglutination response. Considering the presence of various i-antigen types, ability to change i-antigen type in response to corresponding antibody, and relatively low ADCK activity at high agglutination titer, i-antigens of P. dicentrarchi may not be good targets for subunit vaccine development. To develop subunit vaccines against scuticociliatosis, other surface antigens expressed constitutively or expressed specifically under the infection state for survival of the ciliates in the host fish might be more favorable to elicit protective antibodies than the surface i-antigens.     

Interrelationships of the “Ly-6 complex” antigens

Competitive binding studies and immunoprecipitation experiments define at least five distinct epitopes encoded by Ly-6-linked genes—Ly-6A.2, Ly-6B.2, Ly-6C.2, Ly-6D.2, and ThB. Ly-6A.2, a 33 kd protein, and Ly-6D.2 are closely overlapping epitopes that can be distinguished by their unique thymus reactions of 10–20% or >90%, respectively. Similarly, the Ly-6C.2 antigen present on a 14 kd moiety loosely overlaps the Ly-6B.2 antigen. Ly-6C.2 and Ly-6B,2 antigens are distinct from Ly-6A.2 and Ly-6B.2, however. ThB is a 16–18 kd antigen which is not associated on the cell surface with any other Ly-6 antigens. In addition, independently derived antibodies made to the Ly-6C.2 antigen detect an identical epitope, as do antibodies to Ly-6A.2 and Ly-6B.2. These results imply the existence of a single antigenic site on each of these molecules.     

“Weak” histocompatibility antigens generate functionally “strong” humoral immunity

The kinetics and complexity of the immune responses generated by weak histocompatibility antigens on transplants of normal tissues were investigated by analyzing (1) the survival times of test skin grafts on mice that had been initially immunized with skin, liver, or kidney implants, (2) the survival times of test skin grafts on mice that had received putatively immune sera or lymphocytes harvested from an allografted host, and (3) the cytotoxic potential of these cells and sera in vitro. The data indicate that despite chronic rejection, weak antigens rapidly immunize hosts, and that the immune response includes a major humoral component that can either accelerate graft rejection or prolong graft survival.     

A Review of: “Images: A Reader”

Photographs are a ubiquitous feature of Aboriginal life in Northeastern Australia, with images of relatives being prominently displayed in most Aboriginal houses. This display of photographs is tied to a form of distributed personhood that draws on photographs to create a sense of social immediacy in the absence of close kin. This sense of immediacy also occurs in relation to photographs of the dead, giving these images a particular force for Aboriginal viewers. But further consideration of this force of photographic images suggests that they should be treated neither as things nor as aspects of persons, despite their seeming ability to manifest agency in Aboriginal life-worlds.     

Structure and function of ETAA16: a novel cell surface antigen in Ewing’s tumours

Immunoscreening of an Ewing’s family of tumour (EFT)-derived cDNA library using formerly described EFT-specific antibodies led to the isolation of a 3.5 kb cDNA, named Ewing’s tumour-associated antigen 16 (ETAA16). The ETAA16 cDNA shows no homology to any functionally characterised human gene. Only a bovine cDNA expressed in bovine testis and hepatocytes is functionally characterised as it encodes for a junction plaque associated protein and showed a homology of 69.9% at amino acid level to ETAA16. The human cDNA encodes for a 926 amino acid tumour antigen with a calculated molecular weight of 103 kDa. The epitope of the ETAA16-specific antibody, Ak16, covers the central region of the protein which is part of an extra cellular domain. The human ETAA16 gene locus has been assigned to chromosome 2p13-15 by FISH analyses and is confirmed by the human genome sequencing project. As demonstrated by flow cytometry, the cell surface expression of ETAA16 antigen is restricted to ET cell lines and not expressed on other small blue round cell tumours or other kind of tumour. RT-PCR analysis revealed a high expression of ETAA16 in brain, liver and kidney while lung and heart were negative. Immunohistochemistry showed an intracellular expression of ETAA16 in different kind of non-Ewing tumour tissues. These results suggest that ETAA16 may function as a tumour-specific cell surface antigen in EFTs.     

“Chromosome Memory” of Parental Genomes in Embryonic Hybrid Cells

In the hybrid cells obtained by fusion of embryonic stem cells with adult differentiated cells, homologous chromosomes are in two ontogenetic configurations: pluripotent and differentiated. In order to assess the role of cis- and trans-regulation in the maintenance of these states, we studied a set of clones of hybrid cells of the type embryonic stem cells–splenocytes and used two approaches: segregation of parental chromosomes and comparison of pluripotency of the past hybrid cells and embryonic stem cells. The segregation test showed that the hybrid cells lost only the homologs of the somatic partner and this process was sharply accelerated when the cells were cultivated in nonselective conditions, thus suggesting the full or partial preservation of the initial differences in the organization of parental homologs. The descendants of the former hybrid cells, which had the karyotype similar to that of embryonic stem cells, demonstrated the level of pluripotency, comparable with that of embryonic stem cells despite the long-term effect of trans-acting factors from the somatic partner in the genome of hybrid cells. The data obtained are interpreted in the framework of the concept of chromosome memory, in the maintenance of which the key role is played bycis-regulatory factors.     

A Review of: “A White Man's Foot”

While conducting research among the Aran Islanders of Ireland between 1958 and 1968, the author and his wife became aware that their interpretation of Aran culture and personality was at variance with those of filmmakers and writers of fame who had portrayed the Aran milieu in film, books, and plays. This article examines the several reasons why his and his wife's interpretation differs from those, in particular, of Robert Flaherty, John M. Synge, Pat Mullen, and P. A. Ó Síocháin, with special emphasis on the influence of nativism and primitivism on their portrayals. The setting of the article is Ireland of four decades ago and mirrors conditions much different from those of today.     

Immunodominance in the immune response to “multiple” histocompatibility antigens

Cytotoxic effector T cells putatively specific for multiple non-H-2 histocompatibility (H) antigens were generated by immunizing and boosting C57BL/6 and B6.C-H-2 ^dmice with BALB.B and BALB/c stimulator cells, respectively. The generated effectors were tested for cell-mediated lympholysis on a panel of targets whose BALB/c-derived non-H-2 H antigens were donated by CXB recombinant inbred mice. The spectrum of reactivity of cytotoxic effector T cells with CXB targets demonstrated that the effectors did not recognize multiple H antigens but rather preferentially recognized a single immunodominant non-H-2 H antigen. The identity of the immunodominant H antigen was determined by the H-2 genotype of the stimulator cells when (B6 × B6.C-H-2 ^d)F ₁ cytotoxic effectors were tested. These observations indicate that despite the fact that responders were challenged with more than 40 individual non-H-2 H antigens, they preferentially responded to a single immunodominant antigen.     

A mathematical model for embryonic cell division based on a surface “cleavage field”

The process whereby a fertilized egg divides to give rise to an embryo, i.e. the process of cleavage—which can be considered, in some sense, as the early phase of embryonic differentiation—exhibit in many species a precise geometry. Such a geometry may be altered within certain limits, as was done in various classical experiments, and yet normal differentiation may occur. However, since the pattern of cleavage is clearly under genetic control, any model of cleavage should incorporate some device apt to produce a specific geometry. In this paper, a model for embryonic cell division based on a surface “cleavage field” is described. This surface field may be interpreted, for instance, as the surface density of sources of active transport of ions which diffuse into the cell, although other interpretations —such as the surface density of specific binding sites or functional membrane receptors, etc.—are possible. Assumptions relating the geometry of cleavage to the geometry of the level surfaces of the ionic concentration are given together with a discussion of the change in the surface field due to cleavage. Finally, a simplified two-dimensional version of the model is presented which develops interesting patterns of “cleavagerd”, calculated by computer, similar in many ways to those of real threedimensional embryos.