Delayed Hypersensitivity Skin Reactions Research Articles

Neutrophil function during cyclic chemotherapy for cancer disease.

A study of some aspects of granulocyte function was carried out before, during, and after cyclic chemotherapy in 9 patients surgically treated for carcinoma and in 6 patients with very advanced and inoperable cancer. In most patients, total leukocyte mobilization, Candida-stimulated nitroblue tetrazolium dye reduction, and phagocytosis increased after chemotherapy. Furthermore, delayed hypersensitivity skin reactions to PPD and above all to Varidase increased in the same cases. A significant correlation between accumulation of polymorphonuclear leukocytes into skin chambers and skin tests was found in both groups of patients (p less than 0.001). In some instances, fluctuations in the levels of circulating immune complexes without a distinct correlation between these complexes and granulocyte function were found. The data support the hypothesis that depressed granulocyte function may contribute to an increased susceptibility to infections and may be considered an additional factor that favors tumor dissemination. Chemotherapy seems to restore polymorphonuclear function and delayed hypersensitivity skin reactions.

Abnormalities of B cell, helper T and suppressor T cell functions in a patient with common variable hypogammaglobulinemia

Common variable hypogammaglobulinemia (CVH) probably includes a variety of disorders, in that, B cell or helper T cell deficiency and suppressor T cell hyperfunction.A 24-year-old male had had recurrent eczema since his tender age. He had suffered from idiopathic thrombocytopenic purpura(ITP) at 11-year-old, peptic ulcer and colitis at 17-year-old, pyelonephritis at 18-year-old. He suffered from liver damage and ITP at 21-year-old and was given glucocorticoid and thrombocyte infusion. Since Dec' 1980, he was taken pneumonia and low immunoglobulin level was found. The quantitative immunoglobulin levels were IgG 126, IgA, 3, IgM 29, IgD 1 (mg/dl), IgE 14 IU/ml. Peripheral lymphocyte counts were normal and T: B ratio was 72: 26 (control 68: 32). The patient had delayed hypersensitivity skin reactions for PHA and SK-SD. His lymphocytes responded to in vitro stimulation by PHA or Con A.Ig production in vitro by PWM-stimulated lymphocytes from the patient was examined. Co-culture of B cells from the patient and T cells from normal resulted in reduced synthesis of all classes of Ig. Combination of the patient T cells and normal B cells also gave low Ig synthesis and X-ray treatment of the patient T cells did not enhance Ig synthesis. Moreover, coculture of normal lymphocytes and patient T cells resulted in reduced synthesis of Ig. Thus it was demonstrated that poor immunoglobulin synthesis was due to B cell insufficiency, and hypofunction of helper T cells, as well as hyperfunction of suppressor T cells.

Effect of cyclophosphamide on immunological control mechanisms.

Cyclophosphamide (CY) given before immunization causes greatly increased delayed hypersensitivity skin reactions. Increased cell-mediated immunity is associated with depletion of B-lymphocytes from lymphoid tissue and a depression of those lymphocytes whose precursors turn over more rapidly. In the guinea pig, replacement studies showed that the depleted cells were not T-lymphocytes and had immunoglobulin adherent to their surface, a characteristic of B-lymphocytes. Delayed hypersensitivity reactions increased by CY include chemical contact sensitivity, the tuberculin reaction, delayed hypersensitivity to tularemia vaccine and the Jones-Mote reaction to soluble protein antigens. Pretreatment with CY can also increase the antibody response to some antigens, but depress the response to others. In addition, CY has been found to reverse immunological tolerance where this form of unresponsiveness is due to suppressor cells. CY can also enhance the immune response following depression by antigenic competition or desensitization. Other drugs with a similar, but lesser, effect include melphalan, azathioprine and methotrexate.

Delayed hypersensitivity skin reactions in the elderly.

A delayed hypersensitivity response to skin tests was observed in 47 healthy elderly participants in a geriatric screening clinic. Forty‐four subjects (94 per cent) reacted to at least one antigen. It was concluded that anergy is uncommon in the healthy elderly and should not be considered a normal aging phenomenon.

Failure of delayed hypersensitivity skin testing to predict postoperative sepsis and mortality.

Delayed hypersensitivity skin reactions to a battery of recall antigens, haemoglobin and albumin concentrations, arm-muscle circumference, and percentage of ideal weight were determined before operation in 244 patients undergoing elective major surgery. Depressed skin reactions were found in 70 patients (28%), but this group did not have significantly higher sepsis or mortality rates when compared with patients with normal reactions. Significant associations were found between depressed skin reactions and increasing age, anaemia, hypoalbuminaemia, low arm-muscle circumference, and low weight. Patients with benign and malignant disease had similar distributions of skin reactions. Hypoalbuminaemia was associated with a higher rate of serious postoperative sepsis, and hypoalbuminaemia, low arm-muscle circumference, and low weight were all associated with a higher mortality. These results suggest that the routine use of delayed hypersensitivity skin testing in the preoperative assessment of surgical patients is not justified.

The role of polymorphonuclear leukocytes in delayed hypersensitivity skin reactions: suppressive effects of anti-polymorphonuclear leukocyte serum.

Rabbit antisera (APS) against normal guinea pig peritoneal exudate polymorphonuclear leukocytes (PMN), when injected intraperitoneally three times within 24 h into guinea pigs, lead to a marked fall in the blood PMN count (below 100/mm3) 24-72 h after the injection and a mild depression in the number of circulating mononuclear leukocytes (MNC) at 36-72 h. APS treatment of guinea pigs led to a marked suppression of delayed hypersensitivity skin reactions in response to dinitrophenylated bovine gamma-globulin. The volume, induration, mean diameter of the reaction and leukocyte (both PMN and MNC) emigration into local sites were suppressed, as was, to a lesser extent, vascular permeability. Based on these observations it appears that circulating PMN are required for the full expression of delayed hypersensitivity reaction engendered by bovine gamma-globulin.

Immunogenicity of Guinea Pig Cells Transformed in Culture by Chemical Carcinogens<xref ref-type="fn" rid="fn2">2</xref>

The immunogenicity of inbred strain 2/N guinea pig fibroblasts transformed to the malignant state in vitro by chemical carcinogens was evaluated with the use of a variety of in vivo and in vitro methods including delayed-type hypersensitivity skin and tumor transplantation tests and analysis of antibody production by immunofluorescence, complement fixation, and staphylococcal protein A binding tests. Neoplastic transformation was induced by direct treatment of cells in culture with benzo[a]pyrene, 3-methylcholanthrene, or N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) or by the host-mediated method by which fetuses were exposed to diethylnitrosamine or MNNG in vivo prior to cell culture. Rabbits and syngeneic guinea pigs were inoculated with unirradiated and X-irradiated clonally derived cells. Delayed hypersensitivity skin reactions to immunizing or other cells were equivalent in immunized or control guinea pigs, and no protection to tumor outgrowth from a challenge inoculum of immunizing cells was observed. Antibody activity induced in the sera of immunized guinea pigs was cross-reactive and removed by absorption with nontumorigenic cells. Rabbit antisera after absorption with fetal guinea pig cells were nonreactive with the specific immunizing or other culture cells. Chemical carcinogen-induced neoplastic transformation of guinea pig cells can, therefore, occur without formation of detectable, individually distinct cell surface tumor-specific neoantigens.

Cell-mediated immunity and lymphocyte populations in experimental Argentine hemorrhagic fever (Junín Virus)

Guinea pigs infected with the XJ prototype strain of Junín virus reproduce the main features of Argentine hemorrhagic fever, showing hemorrhages, leukothrombocytopenia, and focal lymphoid tissue necrosis. Viral lymphotropism is shown by the presence of viral antigens, severe cytopathic effect, and high virus titers in lymphoid organs. A pronounced depression of humoral immune response to sheep erythrocytes as well as to the virus is described. This study was carried out to determine whether cellular immune response was also modified and which cell populations were affected. Delayed hypersensitivity skin reaction to purified protein derivative was found to be markedly depressed after infection. A noticeable decrease in both percentages and absolute T lymphocyte numbers, detected by E rosettes, in spleen and lymph nodes, together with a low absolute T cell number in peripheral blood, were observed. Total cell counts in spleen, lymph nodes, and peripheral blood were also reduced. On the contrary, no modification in percentages of B lymphocytes, as measured by EAC rosettes, was found. These results indicate that cell-mediated immunity is markedly impaired in guinea pigs infected with the XJ strain of Junín virus. Its relationship with the pathogenesis of the disease is discussed.

The effect of a delayed hypersensitivity skin reaction on in vitro parameters of cell-mediated immunity

The effect of a small dose of antigen, injected intradermally as a simple skin test, on the state of cell-mediated immunity in the guinea pig has been examined. Reduced migration inhibition (MIF) of peritoneal exudate cells (PEC) from animals immunized and skin tested 7 days later was shown against specific and nonspecific antigen and exogenous lymphokine. Lymphocyte cultures from skin-tested guinea pigs showed increased [ 3H]thymidine incorporation when unstimulated by antigen or mitogen. As a result stimulation indices appeared decreased. When sera from skin-tested and non-skin-tested animals were assayed for their migration inhibitory potency against normal PEC, sera from skin-tested animals exhibited a MIF like activity. Evidence for mitogenic activity could also be found when normal unstimulated blood lymphocytes were cultured with 45% skin-tested guinea pig serum in the culture medium. No difference in hemagglutinating antibody titers between skin-tested and non-skin-tested animals was found. It is concluded therefore that a simple skin test may affect the in vitro parameters of cell-mediated immunity and this could be related to a systemic release of lymphokines in vivo.

In vitro monocyte maturation as a prediction of survival in squamous cell carcinoma of the lung.

In vitro monocyte maturation was studied in patients with squamous cell carcinoma of the lung--limited to the ipsilateral hemithorax in 30 and more extensive in 40. The patients were studied prospectively and initial monocyte maturation was correlated with survival. Monocyte maturation in patients with limited disease before treatment ranged from 3.1 to 57.6% with a median value of 21.4%. The survival of those patients in whom monocyte maturation was less than the normal range (less than 30.4%) was significantly shorter than the survival in those with normal maturation ( p less than 0.05). Four of the five patients whose initial maturation was less than 10% proved to be inoperable at surgery. Patients with extensive disease had monocyte maturation ranging from 2.4 to 52.9% with a median value of 13.2%, significantly lower than in those with limited disease (p less than 0.025). Patients with extensive disease and low monocyte maturation survived a significantly shorter time than those with normal maturation ( p less than 0.005). The depression of monocyte development may explain the finding of negative delayed hypersensitivity skin reactions in many patients with lung carcinoma and may prove useful as an index of prognosis.

Pachyonychia congenita with candidiasis.

Summary Pachyonychia congenita in a mother and two siblings, with associated oral candidiasis, is reported. In the propositus lymphocyte stimulation by Candida and delayed hypersensitivity skin reactions to Candida were absent. All other parameters tested were within normal limits. Pachyonychia congenita is a dominantly inherited condition, first described by Jadassohn & Lewandouski in 1906, in which the most constant feature is gross thickening and discolouration of finger and toe nails. Other abnormalities may include palmar and plantar hyper-keratosis, leukoplakia of the tongue and buccal mucous membranes, hyperhidrosis, blistering of the feet and candidiasis. This latter association is described in a mother and two siblings.

In vivo cell mediated immune response to M. tuberculosis and M. salmoniphilum in rainbow trout ( Salmo gairdneri)

The cell mediated immune response to Mycobacterium tuberculosis and Mycobacterium salmoniphilum was studied in rainbow trout ( Salmo gairdneri) by delayed hypersensitivity skin reactions, thymus imprint analysis and a modified skin window assay. Test fish immunized with complete Freund's adjuvant containing M. tuberculosis were compared to control fish which received either incomplete Freund's adjuvant or phosphate buffered saline. Skin testing produced typical delayed hypersensitivity reactions with a significant difference between the test and control fish. Cross reactivity was produced when sensitized fish were tested with M. salmoniphilum. Imprints of thymus tissue from sensitized trout showed a significant shift in cell populations. Skin window studies supported the presence of cell mediated immunity by demonstrating the presence of activated macrophages at the dermal layer.

Prostaglandin E 1 treatment of NZB/W F 1 hybrids—Induction of in vitro and in vivo cell-mediated immune responses to DNA

Female NZB/W F 1 hybrid mice, 4 months of age or older, demonstrate excessive humoral immune responses to native DNA while the expression of cell-mediated immunity (CMI) toward the same antigen is weak. In this study we examined the ability of cells from NZB/W mice to respond with CMI reactions after in vivo or in vitro stimulation with native DNA. In vivo experiments demonstrated that NZB/W mice did not respond to intradermal injections of native DNA with classic delayed hypersensitivity (DH) reactions. Additionally, their splenic lymphocytes did not produce migration inhibitory factor (MIF) following in vitro stimulation with DNA. Significantly, treatment of these animals twice daily with 200 μg Prostaglandin E (PGE 1) markedly altered their CMI responsiveness. PGE 1-treated mice were capable of making delayed hypersensitivity skin reactions to DNA. Histological evaluation of the reaction sites revealed a mononuclear infiltrate in the cutis and subcutis, typical of classic DH reactions. In vitro, a majority (58%) of the spleen cell cultures derived from treated animals released MIF activity following DNA stimulation. Diaflo ultrafiltration of the MIF-containing supernatants showed that the MIF was not due to antigen-antibody complexes, but rather to a true lymphokine. The results of this study provide clear evidence that PGE 1 treatment of NZB/W mice significantly alters the immunological reactivity of these animals toward DNA, one of the antigens implicated in the pathogenesis of systemic lupus erythematosus.

Delayed cutaneous hypersensitivity reaction: Complication of lymphangiography

An unusual delayed hypersensitivity skin reaction developed after lymphangiography to stage the patient's adenocarcinoma of the prostate.

Concurrent and subsequent tumors in the same host: A model to evaluate the host tumor interaction

There is evidence which demonstrates an immune rejection response (IRR) directed against tumor cells in some experimental and human tumors. In the case of FSa-1, a methylcholanthrene-induced fibrosarcoma of the C 3Hf/Sed mouse, the IRR is manifested by a decrease in the dose of radiation expected to control half of the treated tumors (TCD 50) and an increase in the number of tumor cells expected to transplant the tumor in half of the transplanted recipients (TD 50) in immunized hosts. FSaI was transplanted simultaneously in the right and left legs of male and female C 3Hf/Sed mice and each tumor was given 3750 rad when it measured 8 mm. in diameter (viz the TCD 50 value for 8 mm FSaI growing as one isotransplant per animal). The two tumors in any one animal usually responded similarly with either permanent regression or local recurrence after irradiation. In a second experiment, a group of animals received also concurrent tumors. This time an immunogenic FSaI was transplanted in one side and a non immunogenic mammary carcinoma (MDAH-MCaIV) on the opposite side. The tumors were irradiated with TCD 50 doses (3750 rad for FSaI and 6500 for the less radioresponsive MCa). The distribution of local control and recurrence was probabilistic; 50% of the animals exhibited one tumor destroyed and one recurring. In a third experimental group mice were subsequently transplanted with FSaI Mice who showed no recurrence after irradiation of their first FSaI showed a stronger tendency to reject the second implantation than those who previously had local recurrence and subsequent amputation. Retransplants were controlled more easily by irradiation in the group that had been successfully treated for the first transplant. These data indicate that within the inbred population of C 3Hf/Sed mice there is a relatively broad distribution of capacities to react effectively against the FSaI challenge. This was not predicted by the delayed hypersensitivity skin reaction (DHSR) to the FSaI antigen.

Clinical studies on cell-mediated immunity in patients with malignant disease I. Effect of immunotherapy with OK-432 on lymphocyte subpopulation and phytomitogen responsivenessin vitro

Immunotherapy with daily intradermal injections of OK-432, penicillin- and heat-treated lyophilized powder of Su-strain of streptococcus pyogens A3, for over a period of four weeks resulted in quantitative and qualitative effectiveness on impaired cell-mediated immunity even in many patients with far advanced cancer of the stomach or lung. In vitro lymphocyte studies following immunotherapy with OK-432 demonstrated restoration of circulating lymphocyte counts to more than 1,500/microliters, a level associated with normalized subpopulation constitution and increases of phytomitogen blastogenesis. Furthermore, a delayed hypersensitivity skin reaction to PPD was boosted or converted into a positive reaction in some cases. There was, however, no detectable, definite effect on humoral immunity after the therapy. Survival rates at three and six months after the initiation of immunochemotherapy using OK-432 and another chemotherapeutic agent, 5-fluorouracil, in 40 patients with cancer were significantly longer than those of matched control patients given chemotherapy alone.

Kartageners syndrome: a report of six cases with special reference to humoral and cellular immunity.

4 men and 2 women presenting with Kartagener's syndrome were studied. Humoral and cellular immunity were evaluated by measuring immunoglobulin levels, total complement activity, C3, C4 and C5 levels, lymphocyte subpopulations, lymphoproliferative response to PHA, delayed hypersensitivity skin reactions and histocompatibility antigens. The in vitro tests for cellular and humoral immunity showed normal results, or only transitory alterations. However, the in vivo tests clearly showed a decrease in the delayed response in the skin tests using bacterial and mycotic antigens and PPD. In two siblings the HLA typing showed identical haplotypes. The results are presented taking into account the new physiopathogenetic concepts of Karagener's syndrome with respect to dysfunction of the ciliated columnar epithelium and chemotactic defects of the nonciliated blood cells found in these patients.

Reinterpretation of the Dick test: role of group A streptococcal pyrogenic exotoxin

Because of the association of the group A streptococcal pyrogenic exotoxins (SPEs) with erythrogenic toxin used in the classical Dick test, the involvement of the SPEs in production of erythematous skin reactions was assessed. Unless they had been presensitized, young adult rabbits failed to show skin reactions after intracutaneous challenged with SPEs. Rabbits presensitized to purified protein derivative exhibited enhanced skin reactivity when given purified protein derivative plus SPE C; the enhancement was neutralized by antiserum to SPE C. Rabbits sensitized to bovine serum albumin showed extensive red rash development resembling scarlet fever rashes when given bovine serum albumin containing SPE C. Desquamation occurred 5 to 10 days after injection. Animals sensitized to one SPE type showed enhanced skin reactivity to challenge with homologous or heterologous SPE types, indicating the presence of a cross-reactive determinant within the SPE molecules. Repeated challenge of SPE-sensitized animals with homologous toxin resulted in concomitant antitoxin production with reduction of the enhanced skin reactivities, until typical delayed-hypersensitivity skin reactions remained. The data indicate that, in addition to the toxic reaction previously described, SPEs enhance Arthus and delayed-hypersensitivity skin reactions. It follows that erythrogenic toxin represents the enhancement of acquired skin reactivity to streptococcal antigens by one or more SPE types. Therefore, the Dick test measures SPE-enhanced hypersensitivity to streptococcal products.

Rejection of first-set skin allografts in man. the microvasculature is the critical target of the immune response.

Recent reports of microvascular injury in delayed hypersensitivity skin reactions prompted us to reexamine the pathogenesis of first-set skin allograft rejection in man using morphologic techniques that allowed both extensive vessel sampling and unequivocal evaluation of microvascular endothelium. We here report that widespread microvascular damage is a characteristic, early consequence of the cellular immune response to first-set human skin allografts and is qualitatively similar to, but substantially more extensive than, that occurring in delayed hypersensitivity reactions. Microvascular damage in invariably preceded significant epithelial necrosis and affected initially and primarily those venules, arterioles, and small veins enveloped by lymphocytes. Vessels of both the allograft itself and the underlying graft bed (recipient tissue) were equally affected. These data suggest that endothelial cells of the microvasculature are the critical target of the immune response in first-set vascularized skin allograft rejection in man and that rejection can be attributed largely to ischemic infarction resulting from extensive microvascular damage. Other mechanisms, such as direct cellular contacts between infiltrating lymphocytes and epithelium, apparently played only a minor role. The findings presented here indicate that the rejection of first-set vascularized skin allografts, though induced by immunologically specific mechanisms, is primarily effected by final pathways that are relatively nonspecific and that may cause damage to both foreign and host vessels and cells. Rather than contradicting studies demonstrating the exquisite specificity of allograft rejection in other systems, these findings provide a further example of the heterogeneity of the cellular immune response. Recognition of the critical role of immunologically mediated microvascular injury may prove important both for an understanding of the biology of allograft rejection and for strategies aimed at prolonging allograft survival.

Delayed Hypersensitivity Skin Reactions in Patients with Malignant Head and Neck Tumors

Delayed Hypersensitivity Skin Reactions in Patients with Malignant Head and Neck Tumors