Transplant rejection

What is transplant rejection?

Transplantation is the only way to treat many end-stage diseases involving organs like the liver, lungs, heart, and kidneys. (1) However, this life-saving therapy is hindered by transplant rejection, a process whereby the immune system recognizes an allograft as foreign or non-self and initiates a response against it. Hence, the estimated half-life of transplanted organs is less than 15 years and is as low as six years with lung transplants (2).

Transplant rejection is grouped into three major types, depending on how it occurs: hyperacute, acute, and chronic rejection.

Hyperacute rejection happens almost immediately (within 48 hours) after the transplant and only with vascularized grafts (3–5). It results in graft death from clotting in the blood vessels. It is thought to occur because the recipient already has anti-donor antibodies prior to the transplant procedure and is avoidable with ABO matching.

Acute rejection is a common response occurring after all transplants, except between identical twins. It happens when the immune system identifies and attacks an allograft. It may happen from days to months after a transplant, but the risk is highest in the first three months (1). Acute rejection raises the likelihood of developing chronic rejection and lowers allograft half-life by 34% (6).

Chronic rejection is a slow immune response against the grafted organ that progressively damages it until it stops functioning (4). This type of transplant rejection happens months to years after the transplant.

Rejection of allograft transplants relies on the complex interaction of cellular and humoral mechanisms, with T cells being pivotal to its progress. The rejection process is activated through the direct, semi-direct, or indirect pathway (2).

The direct pathway happens when recipient T cells recognize donor major histocompatibility complexes (MHC) intact on donor antigen-presenting cells (7). The indirect pathway happens when recipient antigen-presenting cells acquire, process, and present donor alloantigens as self-restricted peptides on the recipient MHC molecules (5). In the semi-direct pathway, recipient antigen-presenting cells capture donor MHC molecules and present them as intact proteins (8).

What is Graft-Versus-Host Disease?

Graft-versus-host disease (GVHD) is an aggravated inflammatory response activated by graft T cells (9). It occurs when the graft's immune cells identify the recipient’s cells as non-self and attack them (1).

It is the most common complication of allogeneic hematopoietic stem cell transplantation (HSCT), a potentially curative treatment for hematological cancers, including mature T-cell lymphomas and acute leukemia (10). This complication and infection significantly raise the risk of post-transplant disability and death. Over 10% of patients receiving HSCT die from GVHD. GVHD may also occur after a solid organ transplant and transfusion of non-irradiated blood (9).

GVHD is grouped into acute GVHD and chronic GVHD based on clinical manifestations. Acute GVHD occurs in half of transplant recipients and involves the skin, liver, gastrointestinal tract, lungs, kidneys, and eyes (1,10). Chronic GVHD is systemic, with heterogeneous manifestations similar to what occurs with autoimmune diseases.

Signaling pathways involved in transplant rejection and GVHD

The immune system recognizes and differentiates between self and non-self components. It tolerates self and attacks non-self components, leading to graft rejection and GVHD (11).

Current therapies work by suppressing immune system activity. However, immunosuppressive therapies have profound limitations. They are associated with severe complications and side effects, and their efficacy is limited (12). Hence, there is a growing need for more targeted, effective, and safer treatment options. One promising approach is to target signaling pathways involved in transplant rejection and GVHD, such as Notch and JAK signaling.

JAK/STAT signaling is a cell-to-cell communication pathway activated by growth factors and cytokines. It is involved in various biological events, including inflammation and immune system development and function (13). In particular, cytokines that transduct through this pathway regulate the development and functioning of dendritic cells, T cells, neutrophils, and other immune cells necessary for GVHD pathogenesis (14).

JAK signaling is involved in all aspects of the disease process due to its role in immune cell development and function. This makes it a promising target for GVHD treatment. Inhibition of this pathway has been shown to reduce GVHD severity while maintaining an allogeneic immune response against host tumor cells (a phenomenon called graft-versus-leukemia (GVL) activity) (15).

Clinical trials are currently treating GVHD with JAK inhibitors such as itacitinib. The US Food and Drug Administration (FDA) has also approved ruxolitinib for steroid-refractory acute GVHD and ibrutinib for steroid-refractory chronic GVHD. More studies are needed to confirm the effectiveness of JAK inhibitors for GVHD therapy (15).

Notch signaling is a highly conserved signaling pathway involved in many biological processes, including innate and adaptive immune cell development and function (16). It follows that this pathway plays a significant role in immune pathology, including GVHD and allograft rejection and damage (16).

Notch is recognized as a critical inflammatory pathway in T cell alloreactivity, and emerging evidence suggests that inhibiting this pathway can help prevent allograft rejection (12). Notch inhibitors may also be beneficial for treating GVHD without interfering with GVL activity (10).

Other documented signaling pathways implicated in transplant rejection and GVHD include TLR (Toll-Like Receptor) and NF-κB signaling (9). They may also offer a more effective and safer way to prevent transplant rejection and treat GVHD (17). 

References

1. Justiz Vaillant A, Misra S, Fitzgerald B. Acute Transplantation Rejection. [Updated 2023 Jun 12]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023.
2. Cozzi E, Colpo A, De Silvestro G. The mechanisms of rejection in solid organ transplantation. Transfusion and Apheresis Science. 2017;56(4):498-505. doi:10.1016/j.transci.2017.07.005
3. Transplant rejection: MedlinePlus Medical Encyclopedia. Accessed November 13, 2023. https://medlineplus.gov/ency/article/000815.htm
4. Hyperacute Graft Rejection - an overview | ScienceDirect Topics. Accessed November 13, 2023. https://www.sciencedirect.com/topics/medicine-and-dentistry/hyperacute-graft-rejection
5. Moreau A, Varey E, Anegon I, Cuturi MC. Effector mechanisms of rejection. Cold Spring Harb Perspect Med. 2013;3(11). doi:10.1101/cshperspect.a015461
6. Ingulli E. Mechanism of cellular rejection in transplantation. [Updated 2023 Jun 12]. Pediatric Nephrology. 2010;25(1):61-74. doi:10.1007/s00467-008-1020-x
7. Gauthier JM, Li W, Hsiao HM, et al. Mechanisms of graft rejection and immune regulation after lung transplant. Ann Am Thorac Soc. 2017;14(Supplement 3):S216-S219. doi:10.1513/AnnalsATS.201607-576MG
8. Siu JHY, Surendrakumar V, Richards JA, Pettigrew GJ. T cell allorecognition pathways in solid organ transplantation. Front Immunol. 2018;9:2548. doi:10.3389/fimmu.2018.02548
9. Tu S, Zhong D, Xie W, Huang W, Jiang Y, Li Y. Role of toll-like receptor signaling in the pathogenesis of graft-versus-host diseases. Int J Mol Sci. 2016;17(8):1288. doi:10.3390/ijms17081288
10. Di Ianni M, Del Papa B, Baldoni S, et al. NOTCH and graft-versus-host disease. Front Immunol. 2018;9:1825. doi:10.3389/fimmu.2018.01825
11. Li Q, Lan P. Activation of immune signals during organ transplantation. Signal Transduct Target Ther. 2023;8(1):110. doi:10.1038/s41392-023-01377-9
12. Chung J, Riella L V., Maillard I. Targeting the Notch pathway to prevent rejection. American Journal of Transplantation. 2016;16(11):3079-3085. doi:10.1111/ajt.13816
13. Hu X, li J, Fu M, Zhao X, Wang W. The JAK/STAT signaling pathway: from bench to clinic. Signal Transduct Target Ther. 2021;6(1):402. doi:10.1038/s41392-021-00791-1
14. Schroeder MA, Choi J, Staser K, DiPersio JF. The role of Janus kinase signaling in graft-versus-host disease and graft versus leukemia. Biology of Blood and Marrow Transplantation. 2018;24(6):1125-1134. doi:10.1016/j.bbmt.2017.12.797
15. Abboud R, Choi J, Ruminski P, et al. Insights into the role of the JAK/STAT signaling pathway in graft-versus-host disease. Ther Adv Hematol. 2020;11. doi:10.1177/2040620720914489
16. Brandstadter JD, Maillard I. Notch signalling in T cell homeostasis and differentiation. Open Biol. 2019;9(11):190187. doi:10.1098/rsob.190187
17. Molinero LL, Alegre ML. Role of T cell-nuclear factor κB in transplantation. Transplant Rev. 2012;26(3):189-200. doi:10.1016/j.trre.2011.07.005