Transplantation immunology
Gabriel Virella in Medical Immunology, 2019
Graft rejection is the consequence of an immune response mounted by the recipient against the graft, due to incompatibility between tissue antigens of the donor and recipient. Cells that express class-II MHC antigens (such as passenger leukocytes, in the case of solid-organ transplants) play a major role in sensitizing the immune system of the recipient and heightening the potential for graft rejection. These cells also may shed antigen as blood flows through the implanted organ, activating alloreactive helper T lymphocytes from the recipient. This results in the production of interleukin (IL)-2, which leads to clonal expansion, and in turn, multiple immunological and inflammatory phenomena—some mediated by activated T lymphocytes and others mediated by antibodies—which can converge to cause graft rejection.
The Host Response to Grafts and Transplantation Immunology
Julius P. Kreier in Infection, Resistance, and Immunity, 2022
Early attempts at tissue transplantation revealed the existence of strong, immunologic responses that destroy transplanted tissues. These responses effectively eliminate the possibility of tissue transplantation into immunologically competent recipients in the absence of tissue matching or immunosuppression. Since the practice of tissue transplantation is a product of twentieth century medicine, it is difficult to explain the evolutionary significance of an immunologic process designed to prevent tissue exchange, and thus frustrate transplant surgeons. In fact, graft rejection is caused by immunologic mechanisms that are regularly employed to assure survival of the individual by controlling infection. The rejection of foreign tissues is therefore the result of strongly selected and highly conserved immunologic mechanisms, the functions of which are the identification and elimination of “nonself” or foreign, be that infectious agents or transplanta ted foreign tissue.
Cardiovascular system
Brian J Pollard, Gareth Kitchen in Handbook of Clinical Anaesthesia, 2017
A thorough history should be taken with regards to the transplant procedure (including whether an isolated cardiac or heart-lung transplant was performed), and any complications should be sought. Particular attention should be paid to the patient’s current functional status, and review of recent investigations of cardiac function. These may include echo, stress testing, cardiac catheterization and biopsy results. Details of immunosuppressive therapy should be obtained as well as any other medication the patent is taking. If the patient has a PPM or ICD, this should be checked and, if required, reprogramming arranged. If a new history of fever, shortness of breath, ankle swelling, fatigue or palpations is volunteered, graft rejection should be considered and investigated thoroughly.
New horizons in drug discovery of lymphocyte-specific protein tyrosine kinase (Lck) inhibitors: a decade review (2011–2021) focussing on structure–activity relationship (SAR) and docking insights
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Ahmed Elkamhawy, Eslam M. H. Ali, Kyeong Lee
Different studies reported the relation between Lck and other diseases rather than cancer and inflammation; the expression of Lck with Type I diabetes suggesting Lck as one of the main targets for diabetes treatment74. A recent study reviewed the interplay of protein tyrosine phosphatases with Src kinases including Lck establishing their role in auto-immune mediated diabetes75. The concept of Lck inhibition for the management of Type 1 diabetes was supported by another report suggested that βig-h3 represses T cell activation in Type 1 diabetes via inhibition of Lck76. Moreover, blocking of Lck may provide a novel therapeutic target to manage atherosclerosis. A recent study showed T-cells in atherosclerosis patients to be cytotoxic towards vascular smooth muscle cells as well as endothelial cells, leading to vascular injury and plaque destabilisation. Lck might inhibit heat shock protein 65–mediated Reverse Cholesterol Transport in T cells which has been well established as one of the causes involved for atherosclerosis77. Lck was also reported as a potential therapeutic target for acute rejection after kidney transplantation78. Organ graft rejection occurs when the tissue transplanted in the recipient’s body is rejected by his immune system79. Thus, inhibition of Lck has been established as a potential target to prevent organ graft rejection80,81.
TLRs/NLRs: Shaping the landscape of host immunity
Published in International Reviews of Immunology, 2018
Komal Dolasia, Manoj K Bisht, Gourango Pradhan, Atul Udgata, Sangita Mukhopadhyay
TLRs not only detect DAMPs but can also generate DAMPs. LPS activation of TLR4 causes gap junction activation in macrophages and release extracellular UDP, a DAMP, alerting neighboring cells of pathogenic insult.199 Recent research is revealing that inflammation plays a major role in graft rejection. During transplantation, inflammation is triggered either by PAMPs from infection accompanying transplantation or from DAMPs, that are secreted by the graft. These PAMPs or DAMPs are then recognized by TLR/NLR and generate inflammation. Thus, TLRs/NLRs play important roles in mounting immune responses against graft.200,201,202 Hence, these PRRs are being explored for increasing the graft acceptance on transplantation. For example the TLR2 blocking antibody named OPN-305 that reduces inflammation is currently under clinical trial for extended-criteria-donor organs (donor age > 60 years).202
Cemiplimab-rwlc as first and only treatment for advanced cutaneous squamous cell carcinoma
Published in Expert Review of Clinical Pharmacology, 2019
Saqib R. Ahmed, Erik Petersen, Ravi Patel, Michael R. Migden
As previously mentioned, organ transplant patients have an increased risk of advanced CSCC due to their immunosuppression. Currently, having an organ transplant is a relative contraindication in receiving immunotherapy given concerns of transplant rejection (organ transplantation is not a contraindication in FDA approved labeling). In an article by Kittai et al, the authors discuss 12 cases of patients that were treated with immunotherapy in the setting of organ transplant [28]. Of the 12 patients, 4 patients experienced transplant rejection. The 4 patients that experienced transplant rejection received PD-1 blockade and not CTLA-4 blockade [28]. The authors conclude that PD-1 blockade is more detrimental than CTLA-4 blockade for transplant recipients.28 This population will likely need more treatment options in the future. Potential solutions include more targeted immunotherapy versus more focused immunosuppression.
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