Dr. Kuswanto is a physician scientist, board-certified Rheumatologist and instructor in medicine at Stanford University School of Medicine. He is currently working with Garry Nolan, PhD and William Robinson MD, PhD to unravel the tissue immune responses in Rheumatologic diseases. Dr. Kuswanto obtained his medical degree at Harvard Medical School, earning his PhD in Immunology with Diane Mathis and Christophe Benoist where he uncovered the role of the immune system in tissue repair and regeneration. He later moved to Stanford University to complete his residency training and Rheumatology fellowship.
- Tissue inflammation
- Rheumatoid Arthritis
- Sjögren's syndrome
- Internal Medicine
Instructor, Medicine - Immunology & Rheumatology
Honors & Awards
Scientist Development Award (Malawista designation), Rheumatology Research Foundation (2022-2025)
Halstead Holman Rheumatology Research Fellowship Award, Stanford University (2021-2023)
LRP grant, National Institute of Health (2021-2023)
Translational Research and Applied Medicine Award, Stanford University (2021-2023)
Ruth L. Kirschstein NRSA Individual Predoctoral MD/PhD fellowship (F30), National Institute of Allergy and Infectious Diseases (2013-2017)
Board Certification: American Board of Internal Medicine, Rheumatology (2022)
Board Certification, American Board of Internal Medicine, Rheumatology (2022)
Board Certification, American Board of Internal Medicine, Internal Medicine (2020)
Fellowship, Stanford University School of Medicine, Rheumatology (2022)
Residency, Stanford University School of Medicine, Internal Medicine (2019)
M.D., Ph.D., Harvard Medical School, Immunology (2017)
Highly multiplexed spatial profiling with CODEX: bioinformatic analysis and application in human disease.
Seminars in immunopathology
Multiplexed imaging, which enables spatial localization of proteins and RNA to cells within tissues, complements existing multi-omic technologies and has deepened our understanding of health and disease. CODEX, a multiplexed single-cell imaging technology, utilizes a microfluidics system that incorporates DNA barcoded antibodies to visualize 50+cellular markers at the single-cell level. Here, we discuss the latest applications of CODEX to studies of cancer, autoimmunity, and infection as well as current bioinformatics approaches for analysis of multiplexed imaging data from preprocessing to cell segmentation and marker quantification to spatial analysis techniques. We conclude with a commentary on the challenges and future developments for multiplexed spatial profiling.
View details for DOI 10.1007/s00281-022-00974-0
View details for PubMedID 36414691
The Third Dose Is the Charm: Effective Cellular and Humoral Immune Responses to Third COVID-19 Vaccine Doses in Immunosuppressed Nonresponders.
The Journal of rheumatology
Pathogens drive an effective immune response by stimulating the innate immune system, leading to activation of host T and B cells.1 Subsequent pathogen exposure leads to a more robust response through memory T and B cells.
View details for DOI 10.3899/jrheum.220960
View details for PubMedID 36243410
T cell receptor specificity drives accumulation of a reparative population of regulatory T cells within acutely injured skeletal muscle
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2019; 116 (52): 26727–33
Foxp3+CD4+ regulatory T cells (Tregs) play important roles in controlling both homeostatic processes and immune responses at the tissue and organismal levels. For example, Tregs promote muscle regeneration in acute or chronic injury models by direct effects on local muscle progenitor cells, as well as on infiltrating inflammatory cells. Muscle Tregs have a transcriptome, a T cell receptor (TCR) repertoire, and effector capabilities distinct from those of classical, lymphoid-organ Tregs, but it has proven difficult to study the provenance and functions of these unique features due to the rarity of muscle Tregs and their fragility on isolation. Here, we attempted to sidestep these hindrances by generating, characterizing, and employing a line of mice carrying rearranged transgenes encoding the TCRα and TCRβ chains from a Treg clone rapidly and specifically expanded within acutely injured hindlimb muscle of young mice. Tregs displaying the transgene-encoded TCR preferentially accumulated in injured hindlimb muscle in a TCR-dependent manner both in the straight transgenic model and in adoptive-transfer systems; non-Treg CD4+ T cells expressing the same TCR did not specifically localize in injured muscle. The definitive muscle-Treg transcriptome was not established until the transgenic Tregs inhabited muscle. When crossed onto the mdx model of Duchenne muscular dystrophy, the muscle-Treg TCR transgenes drove enhanced accumulation of Tregs in hindlimb muscles and improved muscle regeneration. These findings invoke the possibility of harnessing muscle Tregs or their TCRs for treatment of skeletal muscle pathologies.
View details for DOI 10.1073/pnas.1914848116
View details for Web of Science ID 000504656900081
View details for PubMedID 31822623
View details for PubMedCentralID PMC6936428
TCR Transgenic Mice Reveal Stepwise, Multi-site Acquisition of the Distinctive Fat-Treg Phenotype.
2018; 174 (2): 285-299.e12
Visceral adipose tissue (VAT) hosts a population of regulatory T (Treg) cells, with a unique phenotype, that controls local and systemic inflammation and metabolism. Generation of a T cell receptor transgenic mouse line, wherein VAT Tregs are highly enriched, facilitated study of their provenance, dependencies, and activities. We definitively established a role for T cell receptor specificity, uncovered an unexpected function for the primordial Treg transcription-factor, Foxp3, evidenced a cell-intrinsic role for interleukin-33 receptor, and ordered these dependencies within a coherent scenario. Genesis of the VAT-Treg phenotype entailed a priming step in the spleen, permitting them to exit the lymphoid organs and surveil nonlymphoid tissues, and a final diversification process within VAT, in response to microenvironmental cues. Understanding the principles of tissue-Treg biology is a prerequisite for precision-targeting strategies.
View details for DOI 10.1016/j.cell.2018.05.004
View details for PubMedID 29887374
View details for PubMedCentralID PMC6046274
Rheumatologic symptoms in oncologic patients on PD-1 inhibitors.
Seminars in arthritis and rheumatism
2018; 47 (6): 907-910
Immune checkpoint inhibitors are effective cancer therapies that have been associated with immune-related adverse events (irAEs). Recent reports of irAEs describe symptoms resembling classic rheumatologic syndromes, most notably associated with cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor blockade. Though cases have been described, there are fewer reports of rheumatologic disease associated with programmed cell death protein-1 (PD-1) inhibitors. Here, we describe a series of four patients presenting to the Brigham and Women's Hospital (BWH) Arthritis Center with de novo polymyalgia rheumatica (PMR)-type conditions and/or peripheral synovitis after treatment with PD-1/PD-Ligand 1 (PD-L1) pathway inhibitors.Patients with metastatic renal cell carcinoma (RCC) who were treated with PD-1/PD-L1 pathway inhibitors and subsequently developed complaints of new joint pain were referred to the BWH Arthritis Center as part of routine care and identified retrospectively. The electronic medical record was reviewed for cancer history and treatment, rheumatologic symptoms, physical exam, laboratory testing, and clinical course.All four patients developed irAEs consistent with a PMR-type syndrome and/or peripheral synovitis. Symptoms persisted despite discontinuation of the PD-1/PD-L1 pathway inhibitors; however, three of the patients responded well to oral glucocorticoids alone while one patient required the addition of oral methotrexate. All patients had an eventual decline in inflammatory markers.These cases highlight the need for both oncologists and rheumatologists to recognize the development of rheumatologic disease during treatment with immune checkpoint blockade. Further investigation is needed to optimize the management of irAEs, particularly considering the increasing use of checkpoint inhibitors to treat malignancies.
View details for DOI 10.1016/j.semarthrit.2017.10.018
View details for PubMedID 29191375
Poor Repair of Skeletal Muscle in Aging Mice Reflects a Defect in Local, Interleukin-33-Dependent Accumulation of Regulatory T Cells.
2016; 44 (2): 355-67
Normal repair of skeletal muscle requires local expansion of a special population of Foxp3(+)CD4(+) regulatory T (Treg) cells. Such cells failed to accumulate in acutely injured muscle of old mice, known to undergo ineffectual repair. This defect reflected reduced recruitment of Treg cells to injured muscle, as well as less proliferation and retention therein. Interleukin-33 (IL-33) regulated muscle Treg cell homeostasis in young mice, and its administration to old mice ameliorated their deficits in Treg cell accumulation and muscle regeneration. The major IL-33-expressing cells in skeletal muscle displayed a constellation of markers diagnostic of fibro/adipogenic progenitor cells and were often associated with neural structures, including nerve fibers, nerve bundles, and muscle spindles, which are stretch-sensitive mechanoreceptors important for proprioception. IL-33(+) cells were more frequent after muscle injury and were reduced in old mice. IL-33 is well situated to relay signals between the nervous and immune systems within the muscle context.
View details for DOI 10.1016/j.immuni.2016.01.009
View details for PubMedID 26872699
View details for PubMedCentralID PMC4764071
A special population of regulatory T cells potentiates muscle repair.
2013; 155 (6): 1282-95
Long recognized to be potent suppressors of immune responses, Foxp3(+)CD4(+) regulatory T (Treg) cells are being rediscovered as regulators of nonimmunological processes. We describe a phenotypically and functionally distinct population of Treg cells that rapidly accumulated in the acutely injured skeletal muscle of mice, just as invading myeloid-lineage cells switched from a proinflammatory to a proregenerative state. A Treg population of similar phenotype accumulated in muscles of genetically dystrophic mice. Punctual depletion of Treg cells during the repair process prolonged the proinflammatory infiltrate and impaired muscle repair, while treatments that increased or decreased Treg activities diminished or enhanced (respectively) muscle damage in a dystrophy model. Muscle Treg cells expressed the growth factor Amphiregulin, which acted directly on muscle satellite cells in vitro and improved muscle repair in vivo. Thus, Treg cells and their products may provide new therapeutic opportunities for wound repair and muscular dystrophies.
View details for DOI 10.1016/j.cell.2013.10.054
View details for PubMedID 24315098
View details for PubMedCentralID PMC3894749
Angiotensin II drives the production of tumor-promoting macrophages.
2013; 38 (2): 296-308
Macrophages frequently infiltrate tumors and can enhance cancer growth, yet the origins of the macrophage response are not well understood. Here we address molecular mechanisms of macrophage production in a conditional mouse model of lung adenocarcinoma. We report that overproduction of the peptide hormone Angiotensin II (AngII) in tumor-bearing mice amplifies self-renewing hematopoietic stem cells (HSCs) and macrophage progenitors. The process occurred in the spleen but not the bone marrow, and was independent of hemodynamic changes. The effects of AngII required direct hormone ligation on HSCs, depended on S1P(1) signaling, and allowed the extramedullary tissue to supply new tumor-associated macrophages throughout cancer progression. Conversely, blocking AngII production prevented cancer-induced HSC and macrophage progenitor amplification and thus restrained the macrophage response at its source. These findings indicate that AngII acts upstream of a potent macrophage amplification program and that tumors can remotely exploit the hormone's pathway to stimulate cancer-promoting immunity.
View details for DOI 10.1016/j.immuni.2012.10.015
View details for PubMedID 23333075
View details for PubMedCentralID PMC3582771
IL-7 receptor blockade reverses autoimmune diabetes by promoting inhibition of effector/memory T cells.
Proceedings of the National Academy of Sciences of the United States of America
2012; 109 (31): 12668-73
To protect the organism against autoimmunity, self-reactive effector/memory T cells (T(E/M)) are controlled by cell-intrinsic and -extrinsic regulatory mechanisms. However, how some T(E/M) cells escape regulation and cause autoimmune disease is currently not understood. Here we show that blocking IL-7 receptor-α (IL-7Rα) with monoclonal antibodies in nonobese diabetic (NOD) mice prevented autoimmune diabetes and, importantly, reversed disease in new-onset diabetic mice. Surprisingly, IL-7-deprived diabetogenic T(E/M) cells remained present in the treated animals but showed increased expression of the inhibitory receptor Programmed Death 1 (PD-1) and reduced IFN-γ production. Conversely, IL-7 suppressed PD-1 expression on activated T cells in vitro. Adoptive transfer experiments revealed that T(E/M) cells from anti-IL-7Rα-treated mice had lost their pathogenic potential, indicating that absence of IL-7 signals induces cell-intrinsic tolerance. In addition to this mechanism, IL-7Rα blockade altered the balance of regulatory T cells and T(E/M) cells, hence promoting cell-extrinsic regulation and further increasing the threshold for diabetogenic T-cell activation. Our data demonstrate that IL-7 contributes to the pathogenesis of autoimmune diabetes by enabling T(E/M) cells to remain in a functionally competent state and suggest IL-7Rα blockade as a therapy for established T-cell-dependent autoimmune diseases.
View details for DOI 10.1073/pnas.1203692109
View details for PubMedID 22733744
View details for PubMedCentralID PMC3411948
Cutting Edge: Mechanisms of IL-2-Dependent Maintenance of Functional Regulatory T Cells
JOURNAL OF IMMUNOLOGY
2010; 185 (11): 6426-6430
IL-2 controls the survival of regulatory T cells (Tregs), but it is unclear whether IL-2 also directly affects Treg suppressive capacity in vivo. We have found that eliminating Bim-dependent apoptosis in IL-2- and CD25-deficient mice restored Treg numbers but failed to cure their lethal autoimmune disease, demonstrating that IL-2-dependent survival and suppressive activity can be uncoupled in Tregs. Treatment with IL-2-anti-IL-2-Ab complexes enhanced the numbers and suppressive capacity of IL-2-deprived Tregs with striking increases in CD25, CTLA-4, and CD39/CD73 expression. Although cytokine treatment induced these suppressive mechanisms in both IL-2(-/-) and IL-2(-/-)Bim(-/-) mice, it only reversed autoimmune disease in the latter. Our results suggest that successful IL-2 therapy of established autoimmune diseases will require a threshold quantity of Tregs present at the start of treatment and show that the suppressive capacity of Tregs critically depends on IL-2 even when Treg survival is independent of this cytokine.
View details for DOI 10.4049/jimmunol.0903940
View details for Web of Science ID 000284311500006
View details for PubMedID 21037099
View details for PubMedCentralID PMC3059533
The Initial Phase of an Immune Response Functions to Activate Regulatory T Cells
JOURNAL OF IMMUNOLOGY
2009; 183 (1): 332-339
An early reaction of CD4(+) T lymphocytes to Ag is the production of cytokines, notably IL-2. To detect cytokine-dependent responses, naive Ag-specific T cells were stimulated in vivo and the presence of phosphorylated STAT5 molecules was used to identify the cell populations responding to IL-2. Within hours of T cell priming, IL-2-dependent STAT5 phosphorylation occurred primarily in Foxp3(+) regulatory T cells. In contrast, the Ag-specific T cells received STAT5 signals only after repeated Ag exposure or memory differentiation. Regulatory T cells receiving IL-2 signals proliferated and developed enhanced suppressive activity. These results indicate that one of the earliest events in a T cell response is the activation of endogenous regulatory cells, potentially to prevent autoimmunity.
View details for DOI 10.4049/jimmunol.0900691
View details for Web of Science ID 000275119400037
View details for PubMedID 19542444
View details for PubMedCentralID PMC2753472
Distinct roles of helper T-cell subsets in a systemic autoimmune disease.
2009; 113 (2): 389-95
Imbalance of T-helper cell (Th) differentiation and subsequent cytokine dysregulation is implicated in inflammatory and autoimmune diseases. In particular, 2 cytokines produced by different Th cell populations, interferon-gamma (IFN-gamma) and interleukin-17 (IL-17), have been shown to play a critical role in autoimmunity. We have examined the roles of these cytokines in a mouse model of systemic autoimmunity resulting from the deletion of IL-2 in which autoimmune hemolytic anemia (AIHA) is a prominent feature. We demonstrate that, in IL-2-knockout (KO) BALB/c mice, elimination of the Th1 cytokine, IFN-gamma, delays the development of AIHA. Further, CD4(+) T cells from IL-2/IFN-gamma-KO mice produce elevated levels of IL-17 compared with wild-type (WT) and IL-2-KO, and these mice eventually develop intestinal inflammation. In contrast, elimination of the Th17 cytokine, IL-17, from IL-2-KO mice fails to suppress early acute AIHA development. These results suggest that in a systemic autoimmune disease with multiple manifestations, Th1 cells drive the early autoantibody response and IL-17-producing cells may be responsible for the more chronic tissue inflammation.
View details for DOI 10.1182/blood-2008-04-153346
View details for PubMedID 18815283
View details for PubMedCentralID PMC2615653