Lymphoid Neogenesis in Murine Cardiac Allografts Undergoing Chronic Rejection

Lymphoid neogenesis is the process by which ectopic lymphoid accumulations that resemble lymph nodes arise in nonlymphoid tissues. Such lymphoid accumulations, known as tertiary lymphoid organs (TLO), are observed in chronic autoimmunity and they propagate immune pathology by setting up local antigen presenting sites. Whether lymphoid neogenesis occurs in transplanted organs and contributes to rejection is not well understood. To begin to address this question, we retrospectively analyzed 319 murine cardiac allografts for microscopic evidence of lymph-node-like structures. We found 78 allografts that had either classical TLO, characterized by discrete T- and B-cell zones and high endothelial venules (HEV) expressing peripheral node addressin (PNAd) (n = 34), or PNAd(+) HEV without organized lymphoid accumulations (n = 44). These changes were present in both short- and long-lived allografts and were invariably associated with rejection. Importantly, they occurred in 78% of allografts undergoing chronic rejection (n = 85) but in only 7% of allografts undergoing primarily acute rejection (n = 184). These findings indicate that, like autoimmunity, alloimmunity is associated with lymphoid neogenesis in the target organ and suggest a role for local T-cell activation in chronic allograft rejection.     

Presence of beta human papillomaviruses in nonmelanoma skin cancer from organ transplant recipients and immunocompetent patients in the West of Scotland

Background  Nonmelanoma skin cancer (NMSC) has been linked to cutaneous human papillomaviruses of the genus beta (betaPV).
Objectives  We sought to assess the presence of betaPV in NMSC biopsies from a group of Scottish skin cancer patients, both immunocompetent (IC) patients and immunosuppressed (IS) organ transplant recipients.
Methods  One hundred and twenty-one paraffin-embedded skin tumours (27 actinic keratosis, 41 intraepidermal carcinoma, 53 squamous cell carcinoma) and 11 normal skin samples were analysed for the presence of betaPV by a polymerase chain reaction–reverse hybridization assay designed to detect the presence of the 25 known betaPV genotypes.
Results  In IC patients, betaPV was detected in 30 of 59 (51%) tumours and two of 11 (18%) normal skin samples ( P  =   0·046). In IS patients, betaPV was found in 27 of 62 (44%) tumours; no normal skin samples were available for comparison. The most frequently found genotypes were HPV-24, HPV-15 and HPV-38. Of those tumours infected with betaPV, 28 of 57 (49%) were infected with more than one genotype (range 2–8). Tumours from IS patients were from a younger age group (mean age 57·4 years) than IC patients (mean age 73·8 years). Multiple infections were more common in tumours from IC patients (21 of 30; 70%) compared with those from IS patients (seven of 27; 26%) ( P  <   0·001). In the IC group, age did not appear to influence the distribution of single and multiple infections whereas in IS patients the proportion of multiple infections to single infections increased with age. There were no multiple infections in normal skin.
Conclusions  A wide spectrum of betaPV types was detected in our samples. Further characterization of betaPV in vivo is needed in order to determine the mechanisms by which the virus contributes to cutaneous carcinogenesis.     

Role of the vitamin D3 pathway in healthy and diseased skin – facts, contradictions and hypotheses

Abstract: Irradiation of human keratinocytes with UVB (280–320 nm) in vitro and in vivo activates the metabolism of 7‐dehydrocholesterol to hormonally active calcitriol. The production of calcitriol in the skin strongly depends on the photosynthesis of vitamin D₃ which is biologically inactive in the first instance. Vitamin D₃ serves as the starting substrate for two subsequent enzymatic hydroxylation steps in epidermal keratinocytes. Both the amount of vitamin D₃ and the activity of anabolic and catabolic vitamin D hydroxylases determine the cutaneous level of calcitriol. The hormonally active metabolite of vitamin D₃ regulates a huge number of genes in keratinocytes, and thus acts in an autocrine and/or paracrine manner. This local pathway of vitamin D₃ is unique, but its relevance for healthy and diseased skin is widely unknown, yet. Experimental findings implicate several questions: ( 1 ) Is UVB‐induced formation of calcitriol involved in regulation of growth and differentaition of epidermal cells as well as immunological and skin protective processes? ( 2 ) What endogenous and exogenous factors including drugs affect the cutaneous vitamin D₃ pathway? From a therapeutical point of view, it has been known for a long time that topical application of calcitriol and its analogs can improve hyperproliferative skin diseases like psoriasis. In spite of many encouraging studies in recent years, the fields of the routinely therapeutical application of calcitriol or vitamin D analogs in dermatology (e.g. treatment of immunological, inflammatory, malignancies and infectious skin diseases) have not been intensified. Why is that?     

A new strategy of delayed long-term prophylaxis could prevent cytomegalovirus disease in (D+/R−) solid organ transplant recipients

Abstract:  Long-term prophylaxis against cytomegalovirus (CMV) started immediately after transplantation in (D+/R−) poses a higher risk of late-onset CMV disease. Delayed CMV prophylaxis could allow a transitory exposure of the immune system to CMV, which would let the immune system mount an adequate CMV-specific cytotoxic response in (D+/R−) patients and confer protection against CMV disease. We included all (D+/R−) solid organ transplant recipients (SOT) performed at our institution (January 3/October 6) who received CMV prophylaxis (mainly with oral valganciclovir) during 100 d. In the first period (until December 4), prophylaxis was initiated immediately after transplantation (conventional prophylaxis: CP). Since January 5, it was initiated after 14 d (delayed prophylaxis: DP). Incidence and severity of CMV disease was compared between both groups. A total of 44 SOT recipients were included (CP: 26 and DP: 18). CMV disease was diagnosed in eight patients (18%), seven of 26 (27%) in the CP group, and one of 18 (5.5%) in the DP group (p = 0.07). CMV colitis was reported in five of 26 patients in the CP group (19%), whereas there were no cases of visceral CMV disease in the DP group (p = 0.048). A 14-d delay in the beginning of long-term prophylaxis against CMV in (D+/R−) is safe and could prevent the onset of late-CMV disease.     

Cytomegalovirus infection and disease in the new era of immunosuppression following solid organ transplantation

Abstract: As the most prevalent pathogen among transplant patients, cytomegalovirus (CMV) affects up to three-quarters of all solid organ transplant recipients. While we have made great strides in preventing CMV infection and disease in the early post-transplant period, late CMV infection and indirect effects due to viral immunomodulation remain problematic. Changing immunosuppression practices, including the increasing use of T-cell depleting induction antibodies, have the potential to affect the risk for CMV infection and disease, even in the face of good prophylactic and preemptive therapy. The purpose of this review article is to discuss the impact of CMV infection on long-term allograft outcomes and to re-evaluate the risks and management strategies for prevention of CMV in the framework of evolving modern immunosuppressive strategies.     

Prior diabetes mellitus is associated with increased morbidity in cystic fibrosis patients undergoing bilateral lung transplantation: an ‘orphan’ area? A retrospective case–control study

Background: The aim of this study was to determine whether pre-existing diabetes mellitus increases the risk of rejection, infection and/or death in cystic fibrosis patients undergoing bilateral sequential single-lung transplantation.
Methods: A retrospective audit of 25 consecutive patients with cystic fibrosis who underwent bilateral sequential single-lung transplantation between 1 January 2003 and 31 December 2005 at a tertiary referral hospital was carried out.
Results: Although 32% patients had diabetes diagnosed before lung transplantation, 92% had random blood glucose levels ≥11.1 mmol/L requiring insulin during admission. Patients with pre-existing diabetes had increased infection-related (3.9 vs 1.2, P = 0.01) and putative rejection-related (1.4 vs 0.5, P = 0.04) hospital admissions post-transplantation compared with those without diabetes pre-transplant. During the period of observation, four of eight patients with a prior diagnosis of diabetes died compared with none of 17 patients without prior diabetes ( P = 0.0055).
Conclusion: Almost all cystic fibrosis patients develop hyperglycaemia after lung transplantation, but patients with prior diabetes have more complication-related admissions to hospital and a higher mortality rate.     

A study of a method for distribution analysis of skin color

Background/aims: The objective and quantitative assessment of the skin is important in medical and cosmeceutical research. Assessment of color is an important element for analyzing the surface of the skin, which is usually determined subjectively by a doctor or using color analysis devices. These devices, however, cannot provide correct color information because color is construed from the mean value of the observation region, and analysis of color distribution is impossible. The purpose of this paper is to develop an objective analysis method to permit skin color measurement of each pixel unit of an image and analyze the distribution of skin surface color. Methods: The Skin Color Distribution Analyzer (SCDA) is an analysis method newly developed at the Research Institute for Skin Image at Korea University. The SCDA system presented in this paper performed a novel form of quantitative and objective analysis of skin color distribution using each pixel color model parameter found in image wavelength information. In this paper, distribution analysis was conducted on normal skin and skin lesions and skin affected by artificially induced irritant contact dermatitis and pigmented nevous. The method selected a grade using a color model parameter. Twenty healthy Korean males participated in this study. A comparative study of the eight anatomical areas was performed, including the exposure and non‐exposure parts and the medial aspect and the lateral aspect of the forearm. A reliability test for the SCDA system was also conducted with a spectrometer (SPEC) using the color analysis method. Results: Each skin lesion was precisely segmented by grade and each parameter hada different statistical significance for results of analysis of distribution in pigmented nevous and the artificially induced irritant contact dermatitis. Parameters L^*, b^*, a^*, and EI showed salient traits. Showed resemble measured result in the SCDA system and the SPEC of normal skin. The exposed site, in comparison with the non‐exposed site, showed a notable difference in the L^* parameter and a significant statistical difference in the x and z parameters, except b^*. The comparison of the medial and lateral aspects of the forearm showed a notable difference in the L^* parameter and a significant statistical difference in the parameters except y and b^*. In the reliability test result using the SCDA system and the SPEC, the SCDA system was highly reliabile in terms of the CV value in all color model parameters. Conclusions: The color distribution analysis method using the SCDA system has revealed an aspect that the existent method of medical research has not shown, and is considered to be more reliable than other methods. This method can provide better study findings because it can be applied to other fields in addition to the medical science field and the ripple effect is thought to be bigger in other science field too.