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Women with triple-negative breast cancer (TNBC) have an increased pathologic complete response rate (pCR; residual disease after neoadjuvant chemotherapy) as compared to women with non-TNBC, and those with pCR have a 90% disease-free survival. However, women with TNBC who do not achieve a pCR have an increased risk of recurrence, decreased overall survival, and post-recurrence survival as compared to women with non-TNBC who do not achieve a pCR. A high priority for clinical research is therefore to increase the pCR rate in breast and axilla with preoperative therapy, as therapeutic options for patients who do not have a pCR are limited. Immunotherapy is an attractive strategy as human BCs can be immunogenic and enhancing the immune effector function may augment the cytotoxic effects of standard therapies. Immunity against tumor antigens can be boosted in cancer patients by vaccination with ex vivo-generated tumor antigen-loaded DCs. Here, we report the extended analysis of a clinical trial on 10 TNBC pts assessing the feasibility of combining cyclin B1/WT1/CEF (antigen)-loaded DC vaccination with preoperative chemotherapy in patients with locally advanced TNBC. Combination of preoperative chemotherapy and intratumoral and subcutaneous autologous DC vaccination led to 70% of combined rate of pCR and residual cancer burden 1 (RCB1). To assess expansion of antigen-specific T cell responses, IFN-g-ELISpot was carried out with PBMCs from baseline (BL) and several time points during vaccine treatment that were cultured with control peptides or with peptide libraries covering vaccine antigens. The expansion of antigen-specific immune responses could be detected at various time points post treatment. Transciptional profiling on blood (Nanostring) and tumors (RNAseq) revealed profound changes in immune transcription signatures. T cell and DC signatures in blood and T cell, inflammation, cytotoxic and cell cycle signatures in pre-chemotherapy breast cancer biopsies were linked with pathological responses in definitive surgery specimens. Taken together, differential gene and immunologic signatures of the pre-treatment breast cancer biopsies distinguish pts who have a pCR vs no pCR and can identify potential therapeutic targets for pts with TNBC. Citation Format: Te-Chia Wu, Joyce O’Shaughnessy, Lee K. Roberts, Jennifer L. Smith, Susan B. Burkeholder, Jennifer Finholt, Jessica Tarnowski, Tuoc Dao, Jeffrey Lamont, Sandra M. Zurawski, Phuong Nguyen, Yuanyuan Wang, Kyung In Kim, Derek Blankenship, Jacob Turner, Xuan Wang, Florentina Marches, Maren K. Levin, Michael Grant, Gerard Zurawski, Virginia Pascual, Jacques Banchereau, Karolina Palucka. Immune and transcriptional signatures of dendritic cell (DC) vaccination combined with chemotherapy in locally advanced, triple-negative breast cancer (TNBC) patients [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-04-10.

Background: Plasminogen activators (PAs) and their regulatory counterparts, PA inhibitors (PAIs), play a role in normal differentiation processes and various pathophysiologic conditions of the epidermis. Normal desquamation of corneocytes from the skin3s surface may, in part, be regulated by the balanced activities of tissue-type PA (tPA) and PAI-2. Salicylic acid (SA) is commonly used to remove the hyperkeratotic tissue of corns, calluses, and verrucae, and it may disrupt intercellular adhesion structures; however, its exact mechanism of keratolytic action is poorly defined. We sought to determine the effects of SA by comparing the levels of PA and PAI messenger RNA (mRNA) in normal skin, untreated corns, and SA-treated corns. Methods: Untreated and SA-treated human corn tissue samples were obtained from patients electing surgery to repair bony defects that underlay their lesions. Histopathologic examination of corns was performed by staining the tissue sections with hematoxylin and eosin and by light microscopy. Polymerase chain reaction was used to compare mRNA expression of PAs and PAIs in normal skin, untreated corns, and SA-treated corns. Results: We demonstrated lower tPA and higher PAI-2 mRNA levels in corn tissue compared with normal skin. In corn tissue treated with SA, the expression of tPA mRNA increased and of PAI-2 mRNA decreased to the levels found in normal skin. Conclusion: An altered balance in tPA and PAI-2 levels contributes to the induction of hyperkeratotic corn tissue and suggests that the keratolytic action of SA is associated with its ability to stimulate proteinase-meditated desquamation processes. (J Am Podiatr Med Assoc 98(5): 345–352, 2008)

Many photo immunological studies have used UV radiation sources that emit nonsolar UV spectral energy and UV doses based on nonimmunological endpoints, e.g. erythema and skin edema. Interpretation of these data has led to misunderstanding when extrapolated to hypothetical effects in humans exposed to solar UV. The purpose of this study was to: (1) establish UV dose response relationships for murine skin edema and immunosuppression, and (2) determine how different UV spectra affect these relationships. Back skin and ear minimum edema doses (MEdD) for Kodacel-filtered FS20 sunlamp UV (290-400 nm) were greater than two-fold higher than those for unfiltered FS20 sunlamp UV (250-400 nm). Xenon are solar simulator UV (295-400 nm) MEdD were > 10-fold higher than those for unfiltered sunlamp UV. Back skin and ear MEdD differed two- to five-fold between C3H/HeN, SWR/J and HRA/Skh-1 mice. The minimum immunosuppression doses (MISD) in C3H mice showed similar UV source spectrum dependence. The solar simulator UV MISD was 5.4- and 1.5-fold higher than for unfiltered and Kodacel-filtered sunlamp UV MISD, respectively. Furthermore, MISD were from 3- to 50-fold higher than the MEdD for the three UV sources. The UV bioeffectiveness spectra indicated that UVC energy (250-290 nm) contributed 12% and 18%, respectively, of the total skin edema and immunosuppression UV energy. These data demonstrate the variability in UV sensitivity among mouse strains, the significant differences between murine MEdD and MISD and how these differences are influenced by nonsolar regions (below 295 nm) of the UV spectrum.

Exposure to subcarcinogenic doses of ultraviolet (UV) radiation suppresses tumor immunity, thus permitting the emergence and growth of highly immunogenic skin cancers in mice. Sunscreens prevent UV carcinogenesis; however, there are conflicting reports regarding their ability to block UV-induced tumor immune suppression. In this study we critically evaluated the effects of UV spectrum and dose on the tumor immune protective capacity of 4 marketed sunscreen lotions with labeled sun protection factors (SPF) 8–45. Effective tumor immune suppression doses (TISD), i.e., the lowest dose tested to induce outgrowth of transplanted nonmelanoma skin tumors in 100% of UV-exposed C3H mice, were established for 3 different UV sources. TISD were significantly lower for unfiltered (FS) and Kodacel-filtered (KFS) UVB-type FS20 sunlamps compared with a filtered xenon arc lamp solar simulator. Sunscreen tumor immune protection levels matched those predicted by their labeled SPF when sunscreen-protected mice were exposed to a fixed TISD of solar simulator UV radiation. SPF 30 and 45 sunscreens also blocked activation of tumor antigen-specific suppressor T-lymphocytes in mice exposed to solar simulator UV radiation. In comparison, sunscreens with SPF ≥ 15 provided partial to complete protection, as measured by tumor incidence, for mice exposed to UV radiation from KFS. All sunscreens tested reduced tumor growth rates in KFS UV-exposed mice. None of the sunscreens tested provided measurable tumor immune protection for mice exposed to FS UV radiation. Thus, sunscreen lotions provide an extent of tumor immune protection consistent with their labeled SPF when appropriate testing conditions are employed. Int. J. Cancer, 71:94–102, 1997. © 1997 Wiley-Liss, Inc.

Ultraviolet (UV) radiation suppresses certain immunologic responses, such as contact hypersensitivity (CH). Some previous studies, using sunlamps emitting nonsolar-spectrum UV or excessive UV doses, have questioned the ability of sunscreens to prevent UV-induced immune suppression. Our study evaluated the immune protection capacities of commercial sunscreen lotions in relation to the effects of UV spectrum and dose. C3H mice were exposed to a fixed UV dose from Kodacel-filtered FS sunlamps that caused maximum Langerhans cell depletion and suppression of CH. Kodacel film blocks UV energy below 290 nm, thus eliminating immune-suppressive effects of UVC (200-290 nm) not present in sunlight. CH was equally suppressed in unprotected and placebo-lotion-treated, UV-exposed mice. Mice protected with sun protection factor (SPF)-15 and SPF-30 sunscreens mounted normal CH responses. SPF-4 and SPF-8 sunscreen-protected mice had CH responses significantly greater than those of unprotected mice. Direct effects of UV spectral differences on the immune protection value of an SPF-15 sunscreen were determined by exposing mice to UV radiation from unfiltered and Kodacel-filtered sunlamps and a 1000-W xenon lamp solar simulator (UV spectrum nearly equivalent to sunlight). The sunscreen immune protection value was 30 times the minimum immune suppression dose for the solar simulator, while being 7.5 times this dose for Kodacel-filtered and 2 times the dose for unfiltered sunlamps. These results demonstrate that commercial sunscreen lotions prevent UV-induced immune suppression at a level exceeding the labeled SPF when tested with an environmentally relevant UV source.

A severe skin inflammatory reaction halted the development of a transdermal device to systemically deliver arecoline, a cholinergic agonist, for use in the management of a human neurological disorder. This report demonstrates that the skin reaction is most likely an allergic contact dermatitis (ACD) exacerbated by inflammation, as characterized by classical immunological tests employing inbred mice: abdominal skin sensitization followed by ear challenge and ear challenge of recipients of lymphoid tissues from previously sensitized donors. Chemical analysis of the parent compound in three vehicles was performed to determine the chemical stability of the prepared solutions and the antigen specificity of the murine ACD response. Arecoline was hydrolyzed to the pharmacologically inactive metabolite, arecaidine, to the greatest extent in aqueous vehicles. ACD reactions were greatest when mice were both topically sensitized and challenged with arecoline. In contrast, arecaidine, the hydrolyzed product, did not have immunological activity, but was capable of producing local inflammation in a dose-dependent manner upon subcutaneous injection. These data support the mechanistic hypothesis that upon absorption into skin, arecoline induces a local inflammatory response and a systemic ACD response. Influx of lymphocytes to an arecoline-treated skin site likely mediate ACD through the combined inflammation produced by arecoline and arecaidine and recognition of arecoline as an immunogen.

This clinical delivery system bridging study evaluated the performance of a single-use disposable, commercial prototype device (designated ND 5.5) for particle-mediated epidermal delivery (PMED) of a nucleic acid vaccine against Hepatitis B virus (HBV). Healthy adults, previously immunized with licensed HBV vaccine, received a single boost vaccination of HBV nucleic acid vaccine administered by ND 5.5 or XR-1, the clinical research device used in previous clinical trials. Similar increases in anti-HBV surface antigen serum antibody titers and cell-mediated immune responses were produced by ND 5.5 and XR-1 when delivering comparable effective doses of the vaccine. The overall intensity of the immune response was lower in those subjects vaccinated with two, rather than 4 administrations of vaccine delivered by ND 5.5. Skin reactions at sites of vaccine administration were equivalent with both devices. This is the first clinical demonstration of the safe and effective PMED of a nucleic acid vaccine with the ND 5.5 device.

Ultraviolet (UV) irradiation causes the immunosuppression of contact hypersensitivity (CH) responses in animals and humans. There are conflicting reports regarding the effectiveness of sunscreens in preventing UV-induced suppression of both local-type CH (induced by the application of the contact sensitizer directly to UV-exposed skin) and systemic-type CH (induced by the application of the contact sensitizer to an unirradiated skin site 3 days after UV exposure). The purposes of this study were as follows: 1. 1. to derive solar simulator UV dose-response curves for the induction of local and systemic CH suppression in C3H mice; 2. 2. to establish minimum immune suppression doses (MISDs) for local and systemic CH; 3. 3. to determine the local and systemic immune protection capacity of two commercial sunscreen lotions with labeled sun protection factors (SPFs) of 4 and 8. Dose-response curves for the induction of local and systemic CH suppression were derived by exposing groups of mice to a range of full-spectrum UV doses (0.37–21.4 kJ m−2) on two consecutive days delivered from a filtered 1000 W xenon arc lamp solar simulator. The MISDs, defined as the lowest dose tested to cause approximately 50% suppression of the normal CH response, were obtained from the dose-response curves. Although the local and systemic immunosuppression dose-response curves were not statistically different, the MISD for local suppression of CH (1.35 kJ m−2) was about fivefold lower than that for systemic CH suppression (6.76 kJ m−2). The MISD was used as the endpoint to determine sunscreen immune protection levels. Both sunscreens, applied at 2 mg cm−2, provided immune protection against the induction of local and systemic CH suppression in mice exposed to an effective UV dose of 1 MISD giventhrough the sunscreen, i.e. 4 MISD to SPF 4 sunscreen-protected mice and 8 MISD to SPF 8 sunscreen-protected mice mounted CH responses that were significantly greater than those elicited in unprotected mice exposed to 1 MISD of solar-simulated UV radiation. The calculated immune protection factors for these sunscreens exceeded the level of protection predicted by their labeled SPFs, i.e. the local immune protection factor of both sunscreens was 15 and the systemic immune protection factors were 8 for the SPF4 sunscreen and 15 for the SPF 8 sunscreen. Our data show that these two sunscreens provide levels of immune protection which exceed the levels predicted by their labeled SPFs in immunoprotection tests conducted in mice exposed to a relevant MISD of UV radiation from a source emitting a UV power spectrum similar to that of sunlight.

Exposure to terrestrial solar (sunlight) ultraviolet radiation (UV) is a primary environmental human health hazard. Reports of increased incidence of skin cancer and reduced levels of UV-filtering atmospheric ozone have raised public awareness and concerns about the health risks associated with UV exposure. Public health education programs focused on reducing the risk of solar UV overexposure advocate avoiding mid-day sun exposure, wearing protective clothing and sunglasses, and applying sunscreen to exposed skin.1 Studies have shown that sunscreens prevent UV-induced sunburn (erythema),2 photoaging,3,4 episodes of recurrent herpes labialis (cold sores),5 DNA damage to skin cells,6–8 development of precancerous actinic keratoses,9,10 as well as initiation11,12 and promotion13 of skin cancers. There is confusion, however, regarding the efficacy of sunscreens to prevent UV-induced immunosuppression, due to conflicting results reported in various published studies.14–41

Expense and inconvenience have restricted the use of the filtered xenon are lamp (solar simulator) as a UV source for conducting large-scale animal studies. Because sunscreen immunoprotective levels are significantly affected by the UV power spectrum of the source it is imperative that a solar simulating source be used for accurate measurements of sunscreen protection levels that are relevant to human LV exposures from sunlight. However, relatively inexpensive sunlamps, e.g. the UVA-340, that emit a UV power spectrum similar to that of a solar simulator are available. Unlike FS-type UVB sunlamps, which have a significant amount of effective immunosuppressive non-solar UV energy at wavelengths below 295 nm, the immunosuppression effectiveness spectrum of UVA-340 sunlamps was nearly identical to that of a solar simulator. The purpose of this study was to evaluate this sunlamp for conducting photoimmunological and sunscreen immune protection studies. Groups of C3H mice were exposed to a range of UVA-340 sunlamp doses (0.25 kJ/m2 to 20.0 kJ/m2) to establish a dose-response curve and determine the minimum immune suppression dose (MISD) for iduction of local-type suppression of contact hypersensitivity (CH). The MISD, defined as the lowest UV dose given to produce approximately 50% suppression of the CH response in mice, was determined to be 1.0 kJ/m2 for UVA-340 sunlamps. Immune protection tests on four marketed sunscreen lotions (sun protection factors [SPF] 4, 8, 15 and 30) were then conducted with UVA-340 sunlamps using MISD as the endpoint. The immune protection factors for these sunscreens were equivalent to the level of protection predicted by their labeled SPF. These results are similar to those we have previously obtained using a solar simulator. We conclude from these data that the immunosuppressive effects of UVA-340 sunlamps are similar to those of a solar simulator; however, further studies are needed to determine if UVA-340, or similar, sunlamps are a viable alternative to the solar simulator for conducting large-scale animal experiments that require a relevant UV solar spectrum.

There are numerous advantages associated with the development of transdermal delivery systems for pharmacologically active drugs and chemicals. Before the potential of transdermal drug delivery can be fully realized, however, researchers are being forced to cope with the problems associated with the development of allergic contact dermatitis and other types of immune responses that can emerge in individuals receiving this form of therapy. This appears to be a unique problem of the transdermal delivery systems since the same agents, given orally or by injection, are accepted by the body without immunological incident. The development of an immune response to a trans dermally delivered drug could have serious implications. It is conceivable that in addition to the immediate problem of allergic contact dermatitis, an immune response could develop that could neutralize the drug's activity. As a result, the sensitized patient may no longer derive any clinical benefit from its usage or that of chemically related compounds. The reasons why and how such skin-associated immune responses are induced, as well as an overview of the skin as an immunologically important organ system, will represent the major focus of this presentation.

Contact hypersensitivity (CH) responsiveness to 2–4-dinitro-l-fluorobenzene (DNFB) is depressed in mice that are sensitized through skin sites exposed to ultraviolet radiation (UVR). This is partially due to a reduction in antigen-presenting cell (APC) activity within UVR-exposed skin, a condition marked by a decrease in the density of ATPase/Ia-positive epidermal cells. The purpose of this study was to correlate the histological and functional recovery of APC activity in the skin of C3H mice exposed to low-dose (4 × 450 J/m 2 ) or high-dose (1 × 15 kJ/m 2 ) UVR with the normalization of CH responsiveness. Skin biopsy specimens taken at various intervals after UVR exposure revealed a rapid recovery in the density of ATPase/Ia positive cells: about 70% of normal by 3 days, and normal after 5 days. Functional analyses showed that lymph node cells obtained from donors that were sensitized with DNFB 3 days after UVR treatment transferred normal ear-swelling responsiveness to nonprimed recipients, thus indicating that APC activity in UVR-exposed skin paralleled the recovery of ATPase/Ia-positive epidermal cells. This suggested that an alternative mechanism causes the persistent depression of CH in mice exposed to UVR. Mice pretreated with indomethacin prior to UVR exposure demonstrated a capacity to elicit CH responses to DNFB, which paralleled the histological and functional recovery of APC in the skin (i.e., normal CH responses were elicited 3 days after exposure to UVR). We conclude from this study that APC activity in the skin recovers rapidly after exposure to UVR, and that a PG-dependent mechanism is responsible for many of the persistent and systemic effects that cause a depression in the CH responsiveness of mice treated with UVR.

Sunscreen preparations containing various chemical UV absorbers, para-aminobenzoic acid (PABA), 2 PABA derivatives, benzophenone or a combination of these were topically applied to the backs of C3H/HeN mice prior to their being irradiated with ultraviolet light in the UVB range. In all cases this treatment was effective in preventing the pathological skin changes associated with UVB irradiation. Histological evaluation of skin biopsies from mice treated with the sunscreen preparations and UVB irradiation showed little or no difference from normals in amount of hyperplasia, melanization or parakeratosis present. These histologic changes were observed in animals receiving UVB irradation in the absence of any sunscreen agent. Pretreatment with the various sunscreen agents did not, however, prevent the induction of tumor susceptibility as measured by the sustained growth of a UV-induced tumor which is immunologically rejected in normal syngeneic mice. These data show a clear distinction between the effects of UVB irradiation leading to histological changes in the epidermis and those leading to the state of tumor susceptibility in mice. The distinction was further corroborated by the finding that epidermal hyperplasia induced by repeated applications of croton oil had no significant enhancing or inducing effects on the induction of tumor susceptibility. In addition, the induction of tumor susceptibility. In addition, the induction of tumor susceptiblity is not due to wavelengths of light less than 320 nm since this effect was abrogated when the UVB radiation was filtered through glass. Possible mechanistic differences between the tumor susceptiblity generated in UVB and photoprotected UVB irradiated animals were observed, however, when we attempted to adoptively transfer the state of tumor susceptibility to normal animals. While it was readily transferable with splenic lymphoid cells from UVB irradiated animals, all attempts to transfer the tumor susceptibility from photoprotected animals have, to date, been unsuccessful.

Ultraviolet radiation (UVR) may be the most prevalent agent that man encounters in his environment. As a result, certain biological adaptations take advantage of the beneficial effects of UVR exposure, e.g. the photoactivation steps involved in vitamin D metabolism. In this regard, UVR plays an important role in maintaining our good health; however, it must be noted that UVR is potentially the most harmful naturally occurring agent in our environment. Thus, it appears that several mechanisms have evolved to protect us against the detrimental effects of UVR overexposure. Although epidermal melaninization or "tanning" may be the most obvious example of these processes, we would argue that adoptive mechanisms within the immune system also provide protection against UVR-induced skin damage. It is now known that UVR affects the distribution and functional activities of various immunocompetent cells within the skin, as well as modifying the production of inflammatory and hematopoietically active cytokines. This review will focus on the known mechanisms involved in the immune modulatory effects of UVR and how adoptive immune responses to UVR-induced skin damage contribute to specific pathological processes.

Recent studies have indicated that the inability of UV-irradiated mice to reject UV-induced fibrosarcomas is, at least in part, due to the presence of suppressor T lymphocytes. These cells appear to exert their influence by inhibiting the functional development of effector cells with specificity for cross-reactive tumor-associated antigens. In these experiments, we present evidence as to the nature of the cell types involved in the immunologic responses elicited against UV-induced tumors. The effector cells capable of establishing a state of tumor immunity are T lymphocytes that appear to lack demonstrable Ia determinants. The regulatory suppressor cells, previously shown to be T lymphocytes, have been determined to be Ia+ and functionally radiosensitive. The in vivo administration of anti-Ia antibody or the exposure of UV-irradiated tumor-bearing animals to low dose gamma radiation was capable of influencing the tumor susceptible state. This type of therapy, theoretically designed to selectively depress suppressor T cell function in vivo, appears to enhance the degree of tumor immunity by removing regulatory influences. We believe that these studies establish the importance of immunoregulatory mechanisms in host-UV tumor interactions.

Rat testicular interstitial tissues contain numerous mononuclear phagocytelike cells. Dispersed testicular tissues are allowed to settle onto a glass substrate and the strongly adherent cells are identified as the same cells that have been described in vivo, based on the retention of an in vivo marker (plutonium). These putative testicular intersitial tissue macrophages (TIMs) have adhesion and cell surface features characteristic of mononuclear phagocytes, as determined by scanning electron microscopy. Immediately after isolation from testicular tissues. TIMs show a strong staining reaction for nonspecific esterase. These cells have Fc and complement receptors and some express la cell- surface antigens. About two thirds of the TIMs phagocytose sheep red blood cells and most of the cells are capable of nonspecific phagocytosis of polystyrene beads. This study demonstrates that the phagocytic cells found in testicular interstitial tissues have morphological, histochemical, phagocytic, and immunological properties characteristic of functionally active mononuclear phagocytes. These results suggest that these resident mononuclear phagocytes may play a role in immune-related functions in the testis.

Structure and function of skin are dependent upon interaction of the cells and matrix components that are unique to skin which, in turn, are dependent upon an interactive message system of cytokines acting over distance. Our laboratory has utilized a system which is sufficiently complex to permit a component of the skin to mature into a functional unit that can be indirectly influenced by cell types inherent to the skin, message over distance.The system, human epidermal cells, maturing into an epidermis on an overlying Millicell-HA membrane in the presence of normal fibroblasts or peripheral blood mononuclear cells in a lower chamber has been used to assess the role of interactive cytokines in skin. Data demonstrate: (a) normal fibroblasts enhance the outgrowth and induce a more organized phenotype in squamous cell carcinoma cells; (b) keratinocytes enhance fibroblast proliferation while squamous cell carcinoma cells suppress fibroblast proliferation, and (c) both activated and nonactivated mononuclear cells affect the outgrowth and organization of the squamous cell carcinoma cell line. It is concluded that cells of the skin, by their mediators, do affect the growth of one another in a highly interactive way.

Evidence is presented to show that mice treated with various regimens of 8-methoxypsoralen followed by exposure to long-wave ultraviolet light (PUVA) are rendered tumor-susceptible when challenged with short-wave ultraviolet light (UVB) induced regressor tumors. These same tumors are readily rejected when implanted into normal syngeneic animals. Similar observations have been made in mice treated with subcarcinogenic doses of UVB, where it was shown that the tumor-susceptible state is mediated by suppressor T lymphocytes. These suppressor T-cells may be generated in response to antigens expressed by UVB damaged skin cells. It is now known that suppressor T-cells generated in mice treated with UVB are la-positive and have specificities for cross-reacting tumor antigens shared by all UVB- induced tumors, which have been tested to date. Our data suggest that, like UVB treated mice, treatment of mice with PUVA results in tumor-susceptibility mediated through the generation of Ia + suppressor cells. Since PUVA treatments appear to generate a suppressor cell response in mice, a possible mechanism by which these treatments act to manage autoimmune type skin diseases, such as vitiligo, is discussed.

The existence of epidermal Langerhans cells, Ia-positive dermal dendritic cells, lymphocytes which can demonstrate epidermitropism, and keratinocytes capable of secreting Interleukin- 1-like molecules, each support the concept that skin can function as an immunologic organ. Such conclusions are further strengthened by the knowledge that both afferent and efferent immune responses can take place exclusively within the skin. The purpose of our study was to evaluate the ability of skin to regulate lymphoid cell recirculation and localization properties. The use of ultraviolet radiation as ah exogenous stimulus resulted in a pronounced redistribution of antigen-presenting cells from central (spleen) to peripheral (skin and lymph node) lymphoid tissues as well as marked increase in the rate of lymphocyte entry into skin draining lymph nodes. This latter condition was due to elevations in the quantitative levels of high endothelial venules present within the peripheral lymph nodes. The ability of epidermal keratinocytes to express Class II molecules is known to be associated with a number of skin diseases. However, the functional significance of this phenomenon is unknown. The results of our studies, employing a nude mouse model, indicate that the expression of Class II molecules by keratinocytes facilitates the movement of Langerhans cell precursors into the epidermis and may also function to enhance lymphocyte entry into the skin. We conclude that nonlymphoid components resident within the skin can influence essential aspects of the adaptive immune response through the production of soluble factors (e.g., Interleukin-1 or through the cellular expression of Class II molecules).

Keratinocyte expression of class II antigens (HLA-DR, human; Ia, murine) is associated with certain cutaneous diseases, especially those marked by the infiltration of immune and inflammatory cells into the skin. It has been shown that interferon-gamma (IFN-gamma) is capable of inducing human keratinocytes to express HLA-DR. Similar results, however, have not been duplicated in murine systems. The purpose of this study was to determine whether IFN-gamma was capable of inducing murine keratinocyte expression of Ia in vivo in an experimental model in which epithelial cells in a variety of organs were shown to express Ia after the i.v. injection of IFN-gamma. Recombinant murine IFN-gamma was injected into BALB/c mice. Biopsies of skin and intestine were analyzed by indirect immunoperoxidase to identify Ia-expressing keratinocytes and mucosal cells, respectively. In terferon-gamma was administered as either:1) a single s.c. injection, 2) multiple i.v. injections of increasing doses (10 3 -10 5 U/d) on 3 consecutive d, or 3) i.p. injections of 5 × 10 4 Ud or 5 × 10 5 Ud on 6 consecutive d. At all i.v. and i.p. injection doses, the intestinal villi mucosal cells were induced to express Ia. Keratinocyte expression of Ia, however, was observed only in animals that received the two higher i.p. doses. Procedures to augment Ia expression, e.g., combined treatment with pertussis toxin, dinitrofluorobenzene, tumor necrosis factor, and indomethacin, did not enhance the ability of IFN-gamma to induce keratinocyte expression of Ia. We conclude that: 1) high doses of IFN-gamma are required to induce murine keratinocyte Ia expression in vivo and 2) low doses of IFN-gamma, although capable of inducing intestinal mucosal cells to express Ia, do not induce keratinocyte Ia expression.

Experiments were conducted to determine the distribution and function of common tumor antigens shared by ultraviolet light (UV)., benz[a]pyrene (BP)-, and methylcholanthrene (MCA)-induced tumors. When lymph node cells were removed from UV, BP, or MCA tumor-immune mice and held in tissue culture for

Gradual rejection of topically engrafted human split-thickness skin grafts (HSTSG) occurred in greater than 90% of congenitally athymic (nude) rats between 21 and 42 days of grafting. Engraftment and rejection of HSTSG is accompanied by a partial restoration of some cell-mediated immune components, the mixed lymphocyte response and lysis of human target cells. Histologic features of the rejection process were those seen in a host-versus-graft reaction. Immunofluorescent analysis of skin undergoing rejection demonstrated IgG at the basement membrane zone in most grafts. Nude rats rejecting HSTSG had circulating IgG which bound to the basement membrane zone and blood vessels of human skin. Nude rats treated with cyclosporine injections for 21 days had an enhanced survival of HSTSG, 120 or more days.