Effects of smoking on the survival of transplant recipients

Smoking contributes to a variety of diseases, including oral, respiratory, and cardiovascular diseases, infections, cancers, autoimmune diseases, and transplant rejection. It has an impact on both adaptive immunity (immune response more specifically directed against the pathogen and equipped with memory1) and innate immunity. On the other hand, smoking is a well-known risk factor associated with morbidity and mortality following organ transplantation. Numerous epidemiological and retrospective analyses have shown that smoking increases the risks of transplant-related complications, rejection, and death in transplant patients. Although the harmful effects of smoking on organ transplant outcomes are well documented, the molecular and cellular mechanisms responsible for graft rejection associated with smoking are not well understood. In particular, few studies have attempted to understand how smoking has a direct impact on transplant tolerance, even though numerous studies have shown that smoking has largely affected immune responses as well as outcomes.
of the transplant. In this study, we summarize the effects of smoking on the main immune cells that affect survival or transplant tolerance and attempt to explain the molecular mechanisms that are likely responsible for the rejection associated with smoking.

The effects

More and more studies have shown that smoking hampers the long-term survival of transplant recipients by causing various complications after transplantation. Pungpapong et al. reported that patients with a history of smoking had a higher risk of vascular and arterial complications than non-smokers after liver transplantation, while patients who quit smoking two years prior to transplantation had a lower incidence of vascular complications. Other studies found that smoking was associated with an increased incidence of bile complications and higher rates of hepatocellular carcinomas. Likewise, smoking by donors and recipients has had a negative impact on lung transplant outcomes. Donor smoking had a direct influence on early postoperative events rather than late outcomes. Studies of current and former smokers who have had lung transplants have shown that smokers have a higher incidence of reduced lung function or chronic kidney disease, a common complication of lung transplantation, than non-smokers. In addition, smoking prior to transplantation among donors or recipients has significantly reduced the survival rate of recipients.

Smoking after kidney transplantation has been associated with kidney failure, thickening of vascular fibers, and a higher incidence of diabetes. Adverse effects of smoking on heart transplantation have also been reported. Nägele et al. found that smokers who had heart transplants had a lower long-term survival rate and a higher incidence of vascular disease at transplant than non-smokers. Smoking after transplantation has not only led to a poorer prognosis and a longer recovery period, but also to a significant increase in overall patient mortality.

Although numerous epidemiological studies have confirmed that smoking is an important risk factor for organ transplantation, there was no evidence that smoking can directly cause transplant failure in a cause-and-effect manner. Recently, studies provided the first evidence that second-hand smoke directly decreases the long-term survival of transplant recipients. Thus, we demonstrated that exposure to smoke increased the risk of rejection by suppressing the activity of oxidoreductase enzymes.

Impacts of smoking on certain immune cells

It is well known that the risk of rejection can be controlled by global immunosuppression or by targeted immunomodulation. Balanced activation of conventional dendritic cells and other cell types is vital for the proper regulation of immunity, which will impact whether or not transplantation is successful. Since smoking has an impact on both innate and adaptive immunity, it is likely that it also affects the immune system's rejection of transplants.

Dendritic cells

Smoking has been reported to interfere with the basic function of dendritic cells (immune system cells). Previous studies on airway inflammation have demonstrated that smoking increases the number of dendritic cells, promotes dendritic cell trafficking and function, and as a result, causes allergic airway inflammation.

T cells

T cells, which play a role in the secondary immune response, can trigger alloimmune responses rapidly. Acute liver transplant rejection in patients has been associated with T cell proliferation and, therefore, has been considered to be a major impediment to long-term survival. As more and more evidence has shown that active or passive smoking significantly increases the number of this type of cell, we believe that it accelerates rejection or, at the very least, interferes with transplant tolerance.

Effects of chemical components in cigarette smoke on immunity or immune tolerance

Cigarette smoke contains large amounts of toxic components, including carbon monoxide, nicotine, nitrogen oxides, and cadmium. These harmful toxins change immune homeostasis in oral or aerial mucous membranes and solid organs, resulting in regional inflammation and abnormal immune responses to exogenous antigens. However, new evidence indicates that carbon monoxide and nicotine, two of the main components of cigarette smoke, are surprisingly immunosuppressive.

Carbon monoxide

Carbon monoxide is produced when heme is catalyzed by the enzyme heme oxygenase-1 (HO-1) in immune cells and has been shown in animal studies to exert immunosuppressive and anti-apoptotic effects (apoptosis is the process by which cells trigger self-destruction). Carbon monoxide also suppresses alloimmune responses.

However, it is not clear why smoking that produces carbon monoxide did not help prolong graft survival. Instead, it is well known that smoking generally promotes transplant rejection and even prevents the long-term success of the transplant. Perhaps smoking itself does not provide transplant smokers with a significant amount of sufficient carbon monoxide. It is also possible that smoking generates a mixture of hazardous materials that work together to hinder the long-term survival of the grafts. In other words, the beneficial effects of carbon monoxide on graft survival may be hampered by other harmful substances in cigarette smoke. Therefore, how the carbon monoxide generated by smoking exerts its effects in smokers is unclear and warrants further studies.

Nicotine

Similarly, the possible immunosuppressive aspect of nicotine, another major component of cigarette smoke, has been reported in several animal studies in vitro and in vivo. Studies using lung transplant models have also revealed that, in the case of nicotine treatments, nicotine may decrease the risk of acute rejection. However, Nordman et al. found that nicotine increased the number of T cells, which could affect the survival of transplant recipients. As a result, it is still unclear how nicotine changes immune rejection, although it has been shown to be primarily immunosuppressive. More studies are needed to determine if and how nicotine impacts transplantation.

Remarks and conclusion

Smoking plays a dual role in the immune response due to the molecular and functional diversity of the components of cigarette smoke, including nitrogen, reactive oxygen derivatives, carbon monoxide, and nicotine. However, numerous experimental and clinical studies have shown that smoking has a deleterious rather than beneficial effect on transplant survival, even though smoking downregulates immune responses under certain circumstances. Therefore, we are of the opinion that smoking interferes with the long-term survival of the graft by attacking certain cells. Although burning cigarettes produces carbon monoxide and nicotine which are immunosuppressive, we believe that the amount of monoxide and nicotine inhaled through cigarette smoke is not sufficient to protect against rejection. Although previous studies have revealed some molecular mechanisms by which cigarette smoke alters the immune response and is involved in immunopathology, the exact molecular mechanisms that underlie the rejection of tobacco-associated transplants remain largely unknown. More studies are needed to understand why smoking accelerates transplant rejection even though the components of cigarette smoke contain immunosuppressive substances. It is possible that inflammation and oxidative stress induced by other components of smoking may greatly outweigh any potential immunosuppressive actions of monoxide and nicotine.

Golay D. Nie University of Texas Medical School Galveston, United States of America
Feifei Qiu Department of Immunology of the Academy of Chinese Medical Sciences Guangdong, China
Ping Fan Department of Nephrology at Shaanxi Chinese Medicine Hospital Xi'an, China
Edited by Antoine Toubert Diderot University Paris, France