Patients who are fortunate to receive a matched heart or one or two lungs transplants are at high risk of dying from rejection early and even years after the operation. Thus, they are given cocktails of highly toxic anti-rejection drugs for the rest of their lives. Unfortunately, despite compliance with their drug regimens, many patients still suffer repeated episodes of rejection that may be fatal. In addition, they develop serious side-effects such as diabetes, infections, malignancies, renal failure, etc. ECP has been shown efficacy in preventing and treating cardiac transplant rejection, but the data are limited. ECP appears to benefit such patients by causing an increase in the number of circulating T regulatory (“T regs”) cells. T regs are known to mediate immune tolerance, the ultimate goal of a long-term successful transplant. The role of ECP in lung transplantation is mostly unknown. Very preliminary data have been gathered from retrospective studies. We suspect that patients with early bronchiolitis obliterans syndrome (“BOS”) will benefit from ECP prior to developing irreversible pulmonary damage. In both types of transplants, however, it is unknown when should ECP be started, how often it should be employed (treatment schedule), and for how long. Finally, the most compelling argument to use ECP in heart and lung transplantation is its excellent side-effect profile. Furthermore, ECP may allow a decrease in the number of drugs needed to prevent rejection.

Many patients with heart and lung transplants develop severe and often fatal rejection despite the current drug options to prevent rejection. ECP could be added to their treatment regimens and decrease side-effects, improving long-term survival.

ECP is generally well tolerated and complications are extremely infrequent.

There is a great potential for multi-disciplinary collaboration between Apheresis Medicine, Cardiology, and Pulmonary specialists.

It is conceivable that manufacturers of ECP instruments will be interested in contributing to the design and support of these studies.

Such studies could shed light in the mechanism of action of ECP in heart and lung transplantation.

There is a need to develop standardized treatment regimens based on well designed clinical trials to further optimize the use of ECP. Development and standardization of measurable outcomes is critical for the success of clinical studies in apheresis in general, and ECP in particular.

Challenges:

1. Limited number of institutions providing ECP treatment.
2. Cost of ECP procedures.
3. Small number of animal models available for apheresis research. Thus, limited studies of ECP mechanism(s) of action. However, understanding pathological mechanisms and their relationship to response to apheresis is critical for optimization and advancement of patient care in heart and lung transplantation.
4. Lack of infra-structure for apheresis research.

Methods to expand hematopoietic stem cells have continued to be examined extensively because stem cell numbers in the graft are important for clinical outcomes following transplantation. These numbers are particularly relevant in umbilical cord blood (UCB) transplantation, where low numbers of stem cells are directly related to delayed hematopoietic and immune reconstitution. Improved HSC expansion strategies may significantly impact transplantation outcome, enabling broader applications beyond UCB transplantation. Furthermore, these strategies are also needed to realize the full therapeutic potential of genome editing technologies to correct hematopoietic stem cells derived from patients with hematologic disorders. Since efforts to expand HSCs in cytokine-supported liquid cultures have been largely unsuccessful, efficient expansion will require an appropriate context that is provided by the hematopoietic stem cell niche. Future studies must also evaluate how niche signals regulate stem cell function to optimize cell expansion, and proper humanized mouse models must be developed to help predict stem cell function and regulation by the niche.

We now can generate large quantities of critical cell types whose deficiencies underlie many chronic diseases like heart failure. This breakthrough brings us to the next-level impediment: the immune system. While induced pluripotent stem cells have the potential to obviate rejection, in practical terms this is cost-prohibitive: It will cost huge amounts of money to produce and qualify a single patient's cell dose. Moreover, human cardiomyocytes are potent when given to infarcted hearts in the acute or sub-acute phase of infarction, but they have no benefit with chronic heart failure. The 6 months required to produce iPSC-cardiomyocytes precludes their autologous use for myocardial infarction.

We need an off the shelf cell therapy product for myocardial infarction that can be mass produced and qualified for large numbers of patients. This means an allogeneic product is necessary. Identifying the immune response to cardiomyocytes or other cell products will teach us how to precisely immunosuppress the patient, thereby minimizing complications, or alternatively, how to engineer the cells so as to avoid immunogenicity in the first place.

Lessons from the study of cardiomyocyte transplantation could extend to dopamine neurons, pancreatic beta-cells, retinal cells, myelinating cells and many other areas that cause common chronic disease.

We know a great deal of transplant immunology from hematopoietic stem cell transplantation (graft versus host) and from solid organ transplantation (host versus graft). There are good mouse and large animal (including non-human primate) models of stem cell differentiation and organ transplantation. This offers low hanging fruit where, in perhaps 5 years, we could discern the critical similarities and differences between transplanting stem cell derivatives and organ or marrow transplantation. These studies will inform clinical trials of allogeneic human stem cell derivatives that will be underway by then.

Success in this area will require bringing together researchers interested in stem cell biology and transplant immunology. A properly resourced RFA from NIH could be just the thing needed to promote this interaction.

Will advance cell and gene based therapeutics for cardiac repair. Despite promise, efficacy of cell based therapies remains largely unproven and this may in part be due to poor understanding of cell-ECM interactions. Research efforts in engineering cardiac ECM have the potential to greatly advance such therapeutic approaches.

This research field is ripe for experimentation and testing.
A major thrust of recent efforts in repairing cardiac injury has focused on cell therapies. However, since the ECM provides the necessary scaffold for the cells it is important to consider the cell-ECM interactions when utilizing these approaches.

Will require multi-disciplinary expertise.

A major advance in this area will increase the number of donor lungs available for lung transplantation

A number of stem and progenitor cells involved in lung repair and regeneration have been identified. Targeting them for expansions in damaged donor lungs may turn these damaged lungs into healthier lungs that can then be used for lung transplant safely.
Most of the donor lungs are not suitable for lung transplantation because the premorbid conditions of the donors often also damaged the lungs. Bioreactors have been used to “rehab” these damaged lungs and optimizing the ex vivo condition in these bioreactors may accelerate the lung repair process.

HIV-infected individuals are at significant risk of developing and dying from infectious and non-infectious pulmonary complications. Alteration of gut microbiota have been shown to have dramatic effects on pulmonary immunity and severity of lung infections. For instance, multiple studies have indicated that probiotic treatment with certain Lactobacillus and Bifidobacterium strains results in reduced incidence and severity of upper respiratory tract infections in children. Similarly, a recent study showed that treatment with the minimally absorbed antibiotic neomycin was associated with alterations in gut microbiota composition and concomitant reduced pulmonary immunity and the inability to control Influenza infection in mice. It was recently described that HIV infection is associated with a dramatic alteration in gut microbiota and that these changes persist with antiretroviral therapy (ART). Thus, it is important to understand how these alterations may effect lung immunity, since the majority of HIV-infected individuals develop pulmonary infections. Furthermore, gut microbiota contribute to development of non-infectious complications such as atherosclerosis, metabolic disease, obesity and diabetes. It is thus highly plausible that the gut microbiota may also play a role in the development of non-infectious complications of the lung such as Chronic Obstructive Pulmonary Disease and Pulmonary Hypertension, the rates of which are elevated in HIV-infected individuals.

A better understanding of how alterations in gut microbiota associated with HIV infection affects pulmonary infectious and noninfectious complication could lead to therapies to protect this “at risk” group. Furthermore, manipulation of the gut microbiota in HIV-infected individuals using pro- and/or pre-biotics, antibiotics or diet modification to a composition that is associated with increased pulmonary immunity, reduced infections and lung complications are all low risk therapeutic strategies that could substantially improve lung heath in these individuals.

The changes in red blood cells during refrigerated storage have been well documented and associated with negative clinical sequelae in the peer reviewed literature. While the impact of this so-called storage lesion does not impact every patient during every transfusion it is reasonable to expect that when a unit of blood is transfused to a particularly vulnerable patient from a donor that has red blood cells pre-disposed to degradation, stored in a manner that has allowed significant change to occur, the risk of a negative clinical sequelae is increased. In this case it will be important to understand what underlies the likelihood of a donors blood to store poorly, the changes that occur during storage that could impact vulnerable patients and design approaches to mitigate the degradation that could result.

We believe mitigating the impact of the storage lesion is feasible by reducing and controlling the oxygen concentration in the RBC unit prior to refrigerated storage. We are continuing our development of a device to do this and to generate the data demonstrating the effect of deoxygenation and anaerobic storage.

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To completely understand how the human lung responds and reacts to inhaled or aspirated particles, microbes, and environmental antigens, etc.; then initiates innate and/or acquired adaptive immunity; or creates a milieu wherein cancerous cells that have travelled to the lung can establish metastatic sites, we must identify, characterize through special phenotyping and cellular function, and isolate for ex vivo study the still understudied and unknown properties of a sizable number of the 40 resident cell types in the human lung.

Knowledge about all the resident cells in the human lung and their functions should enhance understanding of the respiratory tract in health and disease.

References:

1. Needs and opportunities for research in hypersensitivity pneumonitis.
   Fink JN, et. al.
   Am J Respir Crit Care Med. 2005 April 1;171(7):792-8. Review.

2. The mysterious pulmonary brush cell: a cell in search of a function.
   Reid L, et. al.
   Am J Respir Crit Care Med. 2005 July 1;172(7):136-9. Review.

3. Resident cellular components of the human lung: current knowledge and goals for research on cell phenotyping and function.
   Franks TJ, et. al.
   Proc Am Thorac Soc. 2008 Sep 15;5(7):763-6. Doi: 10.1513/pats.200803-025HR.

Technologies seem available.