Chronic rejection

Key Words Allograft transplantation chemokine receptor acute rejection chronic rejection CCR1 CCR5 CXCR3 CXCR1 CXCR2. 

Recently, biologicals such as anti-CD3 monoclonal antibody have been used to combat acute rejection. Chronic rejection usually occurs months or even years after transplantation. It is characterized by thickening and fibrosis of the vasculature of the transplanted organ, involving both cellular and humoral immunity. Chronic rejection is treated with the same drugs as those used for acute rejection. 

Chronic rejection is a major cause of late graft loss and is one of the most important problems that remains to be resolved. While chronic rejection simply may be a slow and indolent form of acute cellular rejection, the involvement of the humoral immune system and antibodies against the vascular endothelium appear to play a role. Persistent perivascular and interstitial inflammation is a common finding in kidney, liver, and heart transplantation. Owing to the complex interaction of multiple drugs and diseases over time, it is difficult to dehneate the true nature of chronic rejection. For example, cytomegalovirus is associated with the development of chronic rejection in both liver and heart transplant recipients. Unlike acute rejection, chronic rejection is not reversible. 

Acute rejection usually occurs within the first year after transplantation and is characterized by an intense cellular immune response within the graft. Acute rejection can usually be treated effectively with anti-inflammatory and anti-T-cell therapies. However, recurrent episodes of acute rejection may result in graft destruction or may lead to the development of chronic rejection. Chronic rejection usually occurs years after transplantation and is manifested by progressive loss of graft function, arteriosclerosis, and fibrosis. Whereas the pathogenesis of chronic rejection is not clear, both immunological and nonimmunological mechanisms seem to be involved (7). Based on the available data, chemokines are most likely to play a role in acute and chronic rejection as indicated schematically in Fig. 1. 

Compare and contrast the types of rejection, including hyperacute, acute, chronic, and humoral. 

ESRD secondary to PCKD and failed previous transplant. One prior renal transplant that occurred in 1995 (received kidney from husband), which failed secondary to chronic allograft nephropathy in 2004 (presumably from multiple rejection episodes within the first few years after transplant). For the previous transplant, the patient was maintained on cyclosporine, mycophenolate, and prednisone. 

The literature on chemokines in transplantation has been extensively reviewed in recent years (7-9). In this chapter, we focus on a limited number of chemo-kine receptors where evidence for a functional role has been verified. From the plethora of chemokine receptors, this has been demonstrated for CXCR1/2 in reperfusion injury and for CCR1, CCR5, and CXCR3 during acute and chronic allograft rejection. 

Labarrere CA, Nelson DR, Park JW. Pathologic markers of allograft arteriopathy insight into the pathophysiology of cardiac allograft chronic rejection. Curr Opin Cardiol 2001 16 110-117. 

Neuringer IP, Chalermskulrat W, Aris R. Obliterative bronchiolitis or chronic lung allograft rejection a basic science review. J Heart Lung Transplant 2005 24 3-19. 

Joosten SA, Sijpkens YW, van Kooten C, Paul LC. Chronic renal allograft rejection pathophysiologic considerations. Kidney Int 2005 68 1-13. 

Gao W, Topham PS, King JA, et al. Targeting of the chemokine receptor CCR1 suppresses development of acute and chronic cardiac allograft rejection. J Clin Invest 2000 105 35-44. 

Ruster M, Sperschneider H, Funfstuck R, Stein G, Grone HJ. Differential expression of beta-chemokines MCP-1 and RANTES and their receptors CCR1, CCR2, CCR5 in acute rejection and chronic allograft nephropathy of human renal allografts. Clin Nephrol 2004 61 30-39. 

Yun JJ, Whiting D, Fischbein MP, et al. Combined blockade of the chemokine receptors CCR1 and CCR5 attenuates chronic rejection. Circulation 2004 109 932-937. 

In sum, Wilkinson focuses his explanatory hypothesis on social anxiety. He links social anxiety to shame, depression and violence, and emphasizes that social anxiety has its roots in perceptions of inferiority, unattractiveness, failure or rejection. This helps explain why health is so closely related to lack of friends, low social status, violence and poor early emotional attachment, all of which are associated with similar patterns of raised basal cortisol levels and attenuated responses to experimental stressors. He concludes, therefore, that social anxiety is a very plausible central source of the chronic anxiety that depresses health standards and feeds into the socioeconomic gradient in health. As he puts it, the most important psychosocial determinant of population health is the levels of the various forms of social anxiety in the population, and these in turn are determined by income distribution, early childhood and social networks (Wilkinson, 1999, p. 60). Thus, social anxiety is suggested as an explanation for the links between health and friendship, health and early emotional development, health and the direct psychosocial effects of low social status, the patterning of violence and health in relation to inequality, and health and social cohesion (Wilkinson, 1999, p. 61). 

A 30-year-old male with a two-year history of chronic renal failure requiring dialysis consents to transplantation. A donor kidney becomes available. He is given cyclosporine to prevent transplant rejection just before surgery What is the most likely adverse effect of this drug ... 

Cohen, N., Chronic skin graft rejection in the Urodela I. A comparative study of first-and-second-set allograft reactions, J. Exp. Zool., 167, 36, 1968. 

The interactions of depressed persons with others play an important role in the etiology of depression. According to Coyne (1976) depressed persons elicit support behaviors intermixed with rejection from others. Brown (1994) found that depression chronicity is related to a lack of social support. We investigated whether observable behaviors (which may reflect support-seeking and giving) in an interaction of depressed patients and others (i.e., partner and stranger) (1) predict depression outcome and (2) discriminate between patient and others interactional patterns. 

Aging (skin and other tissues), myocardial infarct or stroke, inflammation, rheumatoid arthritis, atherosclerosis, pulmonary disorders (asthma and chronic obstructive pulmonary diseases), radiation injury, organ transplant rejection, psoriasis, hypertension, AIDS, multiple types of cancer, neuro-degenerative diseases (Parkinson s), diabetes, muscular dystrophy... 

One of the toxic effects the chronic study is designed to detect is cancer formation. Some toxicologists believe, in fact, that cancer is the only form of toxicity not detectable in 90-day studies Indeed, it is difficult to find many examples of forms of toxicity occurring in chronic studies that were not detectable, at higher doses, in 90-day studies. It appears that, in most cases, the chronic exposure allows the effects that were detected in 90-day studies to be detected at lower doses, but does not reveal new forms of toxicity, except possibly cancer. This is not a sufficiently well-established generalization to support rejection of the need for chronic studies, and, of course, the toxicologist obviously needs to determine whether a chemical can increase the rate of tumor formation. So chronic studies will be around for some time. 

Patients suffering from cystic fibrosis often use various aerosolized drugs. To reduce the viscosity of the mucus in the airways, recombinant human deoxyribonuclease is used. This enzyme is the first recombinant protein that has been developed for specific delivery to the lungs via the airways. It has a local action on the mucus in the airways and its absorption is minimal. Another drug that decreases the viscosity of the mucus is acetylcysteine. Aerosolized antibiotics are a further group of therapeutics that is widely used by cystic fibrosis patients. Solutions of antibiotics like tobramycin or colistin are used in nebulizers to prevent exacerbation of the disease. Pentamidine has been used for the prophylaxis of Pneumocystis pneumonia in patients infected with HIV virus, while chronic rejection of lung transplants provided a reason to develop an aerosol formulation of cyclosporine A. 

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