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Journal of Clinical and
Translational Research ROCK inhibition in chronic rejection

the primary receptor for CCL2. 22-24 Elevated CCL2 levels 5. Conclusion
have been observed in lung biopsies from patients with
idiopathic pulmonary fibrosis, while CCR2 has been We showed that combined treatment with FDA-approved
implicated in promoting hepatic fibrosis in mice. 25,26 Our ROCK2 inhibitors—Rezurock and fingolimod—
data suggest that the combined treatment effectively reprograms macrophages isolated from mice and humans,
blocks the CCL2/CCR2 axis, preventing macrophage shifting them from a highly proliferative, profibrotic state
infiltration into the transplanted organ by reducing both toward a less fibrotic phenotype with reduced activity.
the recruitment signals from macrophages within the Our data also indicate that Rezurock, by being superior
allograft and the responsiveness of bone marrow-derived in preventing fibrosis and enhancing the effect of another
macrophages to these signals. ROCK inhibitor, represents a promising strategy for
preventing chronic rejection, as it targets critical profibrotic
Finally, we found that both drugs, when administered pathways in macrophages. Furthermore, transcriptomic
individually, significantly reduced the expression of analysis revealed significant downregulation of cell cycle-
key profibrotic proteins, including collagen I and TGF- related pathways, indicating that this combination therapy
β, in RAW 264.7 macrophages. While the combined could benefit not only post-transplant patients but also
treatment downregulated collagen I to a similar extent individuals with autoimmune and chronic inflammatory
as the individual treatments, it further enhanced the disorders, where reducing macrophage proliferation is
downregulation of TGF-β. Extensive collagen deposition crucial for disease management.
is a well-established marker of fibrotic tissues, 27,28 whereas
TGF-β secreted by macrophages promotes the fibroblast- We must recognize that in the future, pharmacologic
to-myofibroblast transition. 29,30 intervention will probably not be the only option for
alleviating organ rejection. With the advent of new
Current immunosuppressive regimens in solid organ technologies, such as magnetic nanoparticles that remove
transplantation are largely similar, with only minor harmful antibodies or magnetic devices that affect immune
adjustments based on organ-specific immune tolerance cell trajectories, novel approaches may emerge for managing
and risk of rejection. 31-34 The cornerstone therapy typically both acute and chronic rejection of transplanted organs.
includes a calcineurin inhibitor (CNI), an antiproliferative
agent, and corticosteroids, with some variation in induction Acknowledgments
therapy. 31-34 CNIs block IL-2 transcription by inhibiting
calcineurin, thereby disrupting T-cell proliferation. We acknowledge JC Walter Jr.’s support of the Houston
35
Methodist Transplantation Center. Some of the
Antimetabolites suppress lymphocyte proliferation by
inhibiting purine synthesis and thus DNA replication. transcriptome analysis data presented in this manuscript
36
10
Corticosteroids exert broader effects by inhibiting were published by us before.
nuclear factor kappa-light-chain-enhancer of activated B Funding
cell activation, leading to reduced cytokine production,
adhesion molecule expression, and antigen presentation. None.
37
However, because these regimens do not target the fibrotic
activity of macrophages, they are effective for acute Conflict of interest
rejection but do not reduce or prevent chronic rejection. Malgorzata Kloc is Editor-in-Chief of this journal, but
It is worth noting that, beyond pharmacological was not involved in any way, directly or indirectly, in
interventions aimed at preventing transplant rejection, the editorial and peer-review process for this paper. All
non-pharmacologic methods, such as the application other authors declare that they have no known competing
of magnetic nanoparticles or magnetic devices, have financial interests or personal relationships that could have
emerged as promising novel approaches. 38-40 A recent influenced the work reported in this paper.
study showed that functionalized magnetic nanoparticles Author contributions
could eliminate donor-specific antibodies (DSAs) from
saline, blood, and plasma of healthy donors and sensitized Conceptualization: Malgorzata Kloc, Arijita Subuddhi
patients. DSAs, such as antibodies directed against donor Formal analysis: Malgorzata Kloc, Arijita Subuddhi, Marta
class I human leukocyte antigens (e.g., HLA-A), remain Halasa
a major barrier to kidney transplant success. 41,42 Another Investigation: Arijita Subuddhi, Marta Halasa, Ahmed
possible approach is the magnetic manipulation of the Uosef, Dawei Zou, Henry V. Ubelaker,
macrophage actin cytoskeleton to prevent their infiltration Methodology: Malgorzata Kloc, Arijita Subuddhi, Marta
into transplanted organs. 43-46 Halasa

Volume 11 Issue 5 (2025) 92 doi: 10.36922/JCTR025270036