Willys Kent Silvers
University of Pennsylvania · Rehabilitation Medicine
Active 1949–2016
About
Willys Kent Silvers is a faculty member in the Department of Genetics at the University of Pennsylvania's Perelman School of Medicine. His contact information includes an office located at 705b Scl, Philadelphia, PA 19104, and an email address wsilvers@aol.com. The page indicates his association with the university and his role within the genetics department, but does not provide specific details about his research focus, background, or key contributions.
Research topics
- Biology
- Immunology
- Medicine
- Genetics
- Anatomy
Selected publications
2016-01-01
article1st authorCorrespondingStudies on the survival of histocompatibility-Y antigen (H-Y)-incompatible and skin-specific antigen (Skn)-incom- patible skin grafts in mice, as well as those concerned with the survival of cultured parathyroid allografts in rats, indicate that grafts provoke a strong immune response only if they include do- nor macrophages (or Langerhans cells) or if major histocompati- bility complex-compatible macrophages are available to react with cells bearing the foreign antigens. Although a major histocompatibility complex (MHC) restriction with respect to transplantation antigens has been amply and repeatedly demonstrated in vitro (1-7), there is no direct evi- dence that it plays a role in sensitizing hosts to skin and other organ allografts in vivo (but see refs. 8-10). We provide evi- dence for such a role. We propose that for a graft to provoke a strong immune response, it is essential that some of its trans- plantation antigens be expressed on donor macrophages (or cells of this family) or be presented to the host by macrophages which are MHC-compatible with the graft. Our support for this proposition originates from a series of seemingly unrelated experiments: some concerned with the behavior of skin grafts incompatible with respect to male-spe- cific histocompatibility-Y (H-Y) or skin-specific (Skn) antigens in mice, and others concerned with the behavior of cultured endocrine allografts in rats. The details of the rat experiment are being published elsewhere (11), and most of the data con- cerning H-Y-incompatible grafts originate from a previous study (12). Thus, although what follows will include data from all of these studies, only the experiments involving Skn will be de- scribed in detail.
"Intrinsic" immunological tolerance in allophenic mice. 1967.
PubMed · 2007-04-01 · 5 citations
articleSenior authorMice experimentally derived from pairs of conjoined, undifferentiated, cleavage-stage embryos of different histocompatibility genotypes can retain cells of each strain, which still produce their characteristic antigenic products. The animals are permanently tolerant of cells of both original types, remain free of runt disease, and display a normal and specific immune response to introduction of a foreign antigen. Absence of autoimmunity in development of ordinary animals is explainable by the intrinsic kind of tolerance found here.
The Journal of Immunology · 2007-04-01
articleSenior authorMelanoma Research · 2004-12-01 · 1 citations
articleMelanomas are promising targets for immunotherapy, as they express a number of tissue-specific antigens against which immune responses can be elicited. We have previously described transgenic mice in which malignant cutaneous melanomas are produced. The 1042 melanoma cell line, derived from a primary melanoma in one of these mice, was used here to generate tumours by subcutaneous inoculation in syngeneic animals. All mice injected with 1 x 10(6) cells of the 1042 cell line developed a tumour. CD4+ T cells, CD8+ T cells and macrophages infiltrated the tumours. Treatment with dendritic cells pulsed with peptides from melanogenic proteins slowed tumour growth and resulted in increased numbers of infiltrating lymphocytes and macrophages, expansion of CD4+ T cells specific for 1042 cell antigens, and increased levels of 1042-specific immunoglobulin G1 (IgG1) and IgM in serum. The frequency of cytotoxic T lymphocytes (CTLs) specific for the MART-1 melanocytic antigen did not increase after dendritic cell treatment. Indeed, the presence of CD8+ T cells was apparently not required for the anti-tumour effects: slowing of tumour growth was not abrogated in animals depleted of CD8+ T cells using antibodies, or in syngeneic CD8-/- animals. In contrast, treatment with dendritic cells + peptides was ineffective after depletion of CD4+ T cells and in syngeneic CD4-/- mice. This experimental system therefore provides an opportunity to investigate CD4-dependent anti-tumour effector mechanisms, and for studies designed to activate the quiescent CTLs which infiltrate melanomas.
Elizabeth S. Russell, May 1, 1913 - May 28, 2001.
PubMed · 2002-01-01
articleSenior authorThe Underwhite (uw) Locus Acts Autonomously and Reduces the Production of Melanin
Journal of Investigative Dermatology · 2000-10-01 · 43 citations
articleOpen accessPROGRESS IN THE DETERMINATION OF HISTOCOMPATIBILITY
ASAIO Journal · 1999-01-01
articleExperimental and clinical data currently available suggest that of the various possible ways in which the outcome of organ homotransplantation might be improved upon, the one which holds most immediate promise involves devising a selection procedure capable of excluding gross histoincompatibilities. The various approaches to the problem of tissue typing or matching that are presently being investigated are reviewed from the viewpoint of their underlying principles and their potentialities. These methods include direct grafting tests, serologic procedures aimed at matching or identifying pertinent isoantigenic specificities associated with formed elements of the blood, especially leukocytes, and various extracorporeal biologic assays of the capacity of an intended host's immunologically competent cells to react against the transplantation isoantigens of a possible donor. The latter category of tests includes the normallymphocyte transfer test and the irradiated-hamster test.
PubMed · 1998-04-01 · 38 citations
articleMalignant cutaneous melanomas and metastases were taken directly from in situ lesions of genetically identical (C57BL/6 strain) Tyr-SV40E transgenic mice, and samples were analyzed by Western immunoblotting with antisera specific for the COOH terminus of each of four melanocytic proteins. These were tyrosinase, TRP-1, TRP-2, and Pmel 17/silver. Of the 13 melanomas examined, there were 5 melanotic primary tumors, 5 amelanotic primary tumors, and 3 amelanotic metastases. The melanotic tumors expressed all of the markers to some extent. In contrast, the amelanotic tumors lacked detectable levels of one, two, or three of the proteins, except for an apparently amelanotic tumor sample in which all were expressed, but in which some melanotic cells were likely to have been present. Thus, despite some variability, there is clearly a downward trend in the presence of these proteins as the tumors become amelanotic, a pigmentary change associated with ongoing malignant progression. In the amelanotic tumors, tyrosinase was most often deficient, whereas TRP-2 was most often persistently expressed. These results, obtained from melanomas of syngeneic origin, indicate that tumors in the relatively early stages of malignancy might be more responsive than later-stage tumors to immunotherapy involving an ensemble of antigenic peptides of the tested gene products. Moreover, TRP-2 peptides may be especially useful for therapeutic intervention at the later stages.
Proceedings of the National Academy of Sciences · 1997-07-08 · 8 citations
articleThe expression of cell-specialization genes is likely to be changing in tumor cells as their differentiation declines. Functional changes in these genes might yield unusual peptide epitopes with anti-tumor potential and could occur without modification in the DNA sequence of the gene. Melanomas undergo a characteristic decline in melanization that may reflect altered contributions of key melanocytic genes such as tyrosinase. Quantitative reverse transcriptase-PCR of the wild-type (C) tyrosinase gene in transgenic (C57BL/6 strain) mouse melanomas has revealed a shift toward alternative splicing of the pre-mRNA that generated increased levels of the Delta1b and Delta1d mRNA splice variants. The spontaneous c2j albino mutation of tyrosinase (in the C57BL/6 strain) changes the pre-mRNA splicing pattern. In c2j/c2j melanomas, alternative splicing was again increased. However, while some mRNAs (notably Delta1b) present in C/C were obligatorily absent, others (Delta3 and Delta1d) were elevated. In c2j/c2j melanomas, the percentage of total tyrosinase transcripts attributable to Delta3 reached approximately 2-fold the incidence in c2j/c2j or C/C skin melanocytes. The percentage attributable to Delta1d rose to approximately 2-fold the incidence in c2j/c2j skin, and to 10-fold that in C/C skin. These differences provide a basis for unique mouse models in which the melanoma arises in skin grafted from a C/C or c2j/c2j transgenic donor to a transgenic host of the same or opposite tyrosinase genotype. Immunotherapy designs then could be based on augmenting those antigenic peptides that are novel or overrepresented in a tumor relative to the syngeneic host.
Proceedings of the National Academy of Sciences · 1997-05-13 · 22 citations
articleMelanomas tend to become less pigmented in the course of malignant progression. Thus, as proliferation increases, the tumors are decreasingly characterized by the tissue-specific phenotype of normally differentiated melanocytes. To learn whether the decline in melanization is associated with a shift from constitutive to alternative splicing of some pigment gene pre-mRNAs, melanomas were collected from Tyr-SV40E transgenic mice of the standard C57BL/6 strain. The mRNAs of the tyrosinase gene, which has a key role in melanogenesis, were analyzed by quantitative reverse transcriptase-PCR in 34 samples from 16 cutaneous tumors and 9 metastases. The cutaneous tumors included some cases with distinct melanotic and amelanotic zones, which were separately analyzed. All tyrosinase transcripts found in the melanomas were also found in normal skin melanocytes. However, the Delta1b and Delta1d alternatively spliced transcripts, due to deletions within the first exon, were specifically augmented in most of the tumors over their very low levels in skin; the exceptions were some all-amelanotic tumors in which no tyrosinase transcripts were detected. The level of Delta1b rose as high as 11.3% of total tyrosinase mRNAs as compared with 0.6% in skin; Delta1d reached 4.0% as compared with 0. 8% in skin. Expression of these splice variants was highest in the melanotic components of zonal primary tumors, relatively lower in their amelanotic components, and still lower in all-amelanotic primary tumors and amelanotic metastases. The increase in Delta1b and Delta1d transcripts may be predicted to increase the levels of unusual peptides, which could have antigenic potential in the tumors, especially in the relatively early phases of malignancy. Analyses of the alternative transcripts of other pigment genes may identify additional candidate antigens, ultimately enabling melanoma cells in all phases of the disease to be represented as a basis for immune intervention.
Recent grants
NIH · $1.4M · 1992
NIH · $436k · 1986
Frequent coauthors
- 51 shared
Andrew Zalewski
- 47 shared
R. E. Billingham
- 25 shared
Jack Favor
- 22 shared
Clyde F. Barker
Hospital of the University of Pennsylvania
- 19 shared
Ali Naji
Hospital of the University of Pennsylvania
- 16 shared
Eileen Zhou
- 16 shared
Dwight Stambolian
University of Pennsylvania
- 16 shared
Philip Avner
European Molecular Biology Laboratory
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