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Richard Charles Nairn was the Founding Professor of Pathology and Immunology at Monash University, Melbourne, Australia, from 1963 to 1984. He built an outstanding teaching and research department and inaugurated the first Australian diagnostic laboratory in clinical immunology based at the Alfred Hospital, Melbourne. As the first Chief Examiner in Immunology for the Royal College of Pathologists of Australasia (RCPA) and first Chair of the Joint Specialist Advisory Committee in Immunology for the Royal Australasian College of Physicians (RACP) and the RCPA, he initiated and guided the early years of laboratory and clinical immunology in Australasia. His contributions to immunopathology, particularly in cancer immunology and the technology of immunofluorescence were significant, and he was an excellent Editor and the Associate Editor of Pathology for 17 years. Richard Nairn's legacy to Australian pathology and the RCPA is the vibrant specialty of clinical immunology.

The discovery of P-glycoprotein has revealed a fundamental mechanism by which cancer cells evade chemotherapy and this principle has proven relevant to general cellular defence mechanisms in normal physiology. To date this knowledge has promised to improve current cancer chemotherapy through the manipulation of drug combinations according to the P-glycoprotein status of the tumor. Furthermore, the discovery of inhibitors of the protein may provide new therapeutic tools in the treatment of multidrug resistant neoplasia, provided the benefits are deemed greater than the potential detrimental side effects. When looking towards future therapies, however, we must also consider additional mechanisms which undoubtedly contribute to clinical drug resistance. Complete elucidation of this complex cellular defence network will hopefully translate into therapeutic opportunities to circumvent all mechanisms of multidrug resistance, thus positively impacting on patient survival.

The density of zinc-iodide-osmium (ZIO) positive pulmonary Langerhans dendritic cells (LC) was increased about 20-fold in mice after passive exposure to tobacco smoke. This was associated with pulmonary changes consistent with the cigarette smoking-related clinical syndrome in humans, pulmonary Langerhans cell granulomatosis. The major feature was an interstitial peribronchial granuloma. The cellular infiltrate of the granuloma (lymphocytes, plasma cells, eosinophils, clusters of large histiocyte-like cells and macrophages) extended into the adjacent alveolar septum forming a star-shaped lesion. The histiocyte-like cells were large with pale acidophilic cytoplasm and many ill-defined short dendrites extending from the cell membrane. Bronchial epithelial metaplasia also developed. The interstitial changes were followed by the development of proliferative alveolar and bronchial lesions in 2 mice. The zinc-iodide-osmium positive cells were consistent with la positive pulmonary dendritic cells and their ultrastructure was similar to that of pulmonary Langerhans cells. After ceasing exposure to tobacco smoke the density of pulmonary Langerhans cells returned to that of the control level; interstitial granulomatous lesions disappeared, but the bronchial epithelial metaplasia did not reverse. Tobacco smoke exposure of mice produces interstitial granulomatous inflammation similar to Langerhans cell granulomatosis in humans. The elevated level of pulmonary Langerhans cells implicate these cells in the pathogenesis of these lesions.

The immune status of 29 members of the Australian National Antarctic Research Expeditions (ANARE) was investigated before, during, and after a 56 day summer voyage to Antarctica and correlated with psychological and physiological parameters. All subjects were healthy. Expedition personnel demonstrated decreased cell mediated immune responses (CMI) assessed by the CMI Multi-test; 21% were hypoergic. The major associated observation was a significant negative correlation with anxiety in Antarctica. However, perceived anxiety was greater before and after the voyage. No significant changes were found in T and B lymphocyte subsets, immunoglobulin and complement components and cutaneous blood flow, nor was there any clinical evidence of illness. Of the hormones examined only cortisol was low predeparture which may reflect increased perceived anxiety at that time. Changes in immune control mechanism were apparent as shown by reduced CMI responses and lowered tetanus antibody levels. Stress factors are postulated to induce depression of the immune response in Antarctica. The association with anxiety suggests that brain peptides or associated cytokines may have a role in mediating these immune events. Such alterations in immune status have implications for health management in isolated and extreme conditions.

Antigen presenting S100 positive dendritic cells have been quantified in normal trachea, lung, bronchial lymph nodes, 130 lung tumors and in 100 lymph nodes regional to tumor. Dendritic cells are rarely seen as intraepithelial components of the normal bronchial mucosa, but are more commonly observed in the perivascular lymphoid tissue of the submucosa and in the alveolar septae of normal lung parenchyma (6 +/- 4.85 cells/HPF). The density of these dendritic cells is marked in histologically normal bronchial lymph nodes. Bronchioalveolar (Alveolar II), well and moderately differentiated squamous cell carcinomas contain the highest density of S100 positive dendritic cells, while small cell lung cancer and poorly differentiated squamous cell carcinoma show the lowest density. Regional lymph nodes to lung tumors with lymphocytic predominance and active germinal centres show the highest density of dendritic cells, while unstimulated lymph nodes contain the lowest number of S100 positive dendritic cells. Tumor infiltrating lymphocytes are marked in and around lung tumors with the higher density of dendritic cells. Survival of patients whose tumors contain high density of S100 positive dendritic cells is more favourable compared to tumors with low density of these cells. It is concluded that the density of the antigen presenting S100 dendritic cells in lung tumors is related to subtype, and tumor differentiation. A high dendritic cell density is associated with enhanced patient survival.

Class II major histocompatibility complex (MHC) molecules are only present on Langerhans cells (LC) in normal murine epidermis. Depletion of this antigen with the chemical carcinogen dimethylbenzanthracene (DMBA) causes I-E disparate B10.A(2R) congenic tail skin to be accepted permanently when grafted onto B10.A(4R) recipients. Adoptive transfer of spleen cells from these recipients into naive syngeneic hosts inhibited the ability of the host mice to reject untreated B10.A(2R) tail skin grafts. Hence DMBA-treated LC depleted I-E disparate skin grafts activate suppressor cells which did not inhibit BALB/c mice from rejecting a B10.A(2R) tail skin graft. In contrast, the tobacco derived carcinogen benzo(a)pyrene (BP) increased the number of epidermal LC but had no effect on either class I or class II MHC disparate skin graft survival time. This confirms that the number of class II MHC-positive LC is critical for the initiation of skin graft rejection; when the threshold level is attained graft rejection proceeds at a maximal rate that cannot be enhanced by raising the number of LC. The tolerant skin grafts had increased numbers of LC; this was not observed in syngeneic grafts and therefore may be related to the active suppression of immunity.

Langerhans cells (LC) are dendritic antigen presenting cells of bone marrow origin which reside in the suprabasal layer of the epidermis. They express high concentrations of Class II MHC glycoproteins on their plasma membrane and transport cutaneous antigen to local lymph nodes for presentation to helper T cells. They are thus essential for the induction of cutaneous immunity. Gliotoxin is a member of the epipolythiodioxopiperazine (ETP) group of fungal metabolites, derived from the human pathogen Aspergillus fumigatus. It has been shown to have immunomodulating properties in vivo and in vitro, and has been proposed as a potential immunosuppressant for transplantation therapy. Epicutaneous application of gliotoxin reduced the numbers of epidermal LC by 30-35 per cent with an associated morphological change from highly dendritic to a more rounded form. Electron microscopic studies showed selective damage to LC at very low (nM) concentrations of gliotoxin, with no obvious effect on adjacent keratinocytes. LC numbers remained depleted for 13 weeks after initial treatment, suggesting that systemic suppression or prolonged retention of gliotoxin within the skin may play a role in its mechanism of action.

The quantitative distribution of Langerhans cells (LC) was studied in a range of pre-neoplastic, in-situ and invasive neoplastic skin lesions using an antibody to S100 protein and the indirect immunoperoxidase technique. LC numbers were increased within the lesions of actinic keratosis, Bowen's disease, keratoacanthoma, squamous cell carcinoma and basal cell carcinoma. In all lesions except actinic keratosis the LC density was also significantly increased in the adjacent non-neoplastic epithelium. The increased LC density in neoplastic epithelium suggests either that LC are being retained within the abnormal epithelium for longer periods of time than normal or that increased numbers of LC are being actively attracted by factors produced by the neoplastic epithelium. While reduction of intraepithelial LC density may allow the initiation of neoplasia the increased density observed in this study suggests that at later stages of tumour growth LC may have a functional role in the host response to cutaneous neoplasia.

Baby guinea-pigs were susceptible to infection with Leptospira interrogans serovar pomona, but rapidly became resistant as they matured. Increased resistance with increasing weight of guinea-pigs was correlated with the development of ability to produce agglutinating antibodies to leptospires and with maturation of B-cell dependent (but not T-cell dependent) areas in lymphoid organs. These observations can explain the basis of species-resistance of adult guinea-pigs to infection with serovar pomona.

The basal lamina in a variety of skin tumours was assessed with an antibody to type IV collagen and the peroxidase-antiperoxidase (PAP) technique. The antibody was raised in rabbits against type IV collagen isolated from human placental tissue. The basal lamina in Bowen's disease was essentially intact while squamous cell and basal cell carcinomas showed focal loss in areas of tumour cell invasion. However, both tumours showed preservation of basal lamina around the majority of projections and nests of tumour within the dermis. Many keratoacanthomas showed extensive loss of the basal lamina. This loss appears associated with advanced keratinization at the base of the lesion and may represent an involutional change possibly secondary to inflammation. It is concluded that epidermal tumour cells following local invasion may cease migration and produce a distinct continuous basal lamina similar to that of the normal dermo-epidermal junction. Loss of basal lamina appears restricted to foci of ongoing tumour invasion.

Cryostat sections of livers from rats treated with carbon tetrachloride (CCl4) for 12 weeks were examined by indirect immunofluorescence for reactivity with human serum containing smooth muscle antibody (SMA). Increased binding of SMA serum to hepatocytes was observed as early as the first week of CCl4 treatment and remained enhanced during the 12 weeks of study. No difference in staining intensity was observed between pre-cirrhotic liver parenchymal cells and hepatocytes in regenerative nodules of frankly cirrhotic livers. In addition, granulation tissue fibroblasts in cirrhotic livers showed strong reactivity with SMA serum. The specificity of the staining reaction for actin was established by its prevention on neutralization absorptions of the serum with homogenates of smooth muscle or extracts containing actin derived from smooth muscle. Circulating SMA was not demonstrated in the serum of rats at any phase of the study. The observations show that there is an increased expression of actin-like protein in regenerating hepatocytes and granulation tissue fibroblasts in cirrhotic livers.