T Cell and B Cell Inhibitors – Immunosuppressive Drugs

00:01 This is a discussion of medications that suppress the activity of T cells and or B cells.

00:06 Lymphocyte immunosuppression is essential in managing various autoimmune diseases, transplant rejection, and other conditions.

00:13 The drugs may target only T cells, only B cells, or both.

00:18 T cell inhibitors consist of biologics and calcineurin inhibitors.

00:22 Biologic medications are derived from living organisms or their cells, e.g. monoclonal antibodies, fusion proteins, vaccines, hormones, cytokines.

00:33 Examples of biologics are Abaticept, brand name Arencia, which blocks T cell activation.

00:37 It is used for rheumatoid arthritis.

00:40 Another example is Bolaticept, which decreases the risk of prevents transplant rejection by inhibiting T cell activation.

00:47 Let's examine Abaticept in more detail.

00:50 Orencia is a very commonly used agent in the treatment of rheumatoid arthritis.

00:56 It is a modified antibody.

00:59 It acts through the fusion protein of IgG and it also works through something called the cytotoxic T-lymphocyte associated protein.

01:10 It’s a complex mechanism that acts to reduce inflammation through these agents.

01:16 It is composed of the Fc region of IgG-1 and it’s attached to these - the cytotoxic T-lymphocyte associated protein.

01:28 It prevents cell CD80 molecule which is on the surface of the cell and CD86 from attaching to a T cell so we often then have patients who have T cells that can't be activated. Why is that good? We use it in patients with severe rheumatoid arthritis because in some cases of severe RA people have T cell activation.

01:55 We use it psoriatic arthritis and we can also use it in juvenile idiopathic arthritis.

02:03 Now, Orencia should be used in caution in certain cases.

02:07 A contraindication to the use of Orencia includes pregnant women because it can cause defects in mice in some of our studies.

02:15 We've never actually tested it in human women but it’s not worth the risk if we see it in other mammals.

02:22 It is also transmitted in rodent milk so obviously we don’t want to do the test in humans because we would just expose children to too much high risk.

02:31 Tuberculosis is another potential contraindication because the fight against TB in the human body involves the T cells as part of the [RM -- 01:54], inhibiting the T cells is going to cause TB to let's just say run rampant.

02:47 We should not use this medication in combination with tumor necrosis factor antagonists and that’s because of the severe suppression that you'll get of the immune system so really, be careful using these two agents in combination.

03:01 And finally, the thing that we also should be aware is that slow growing cancers can spread in the presence of Orencia.

03:09 Now, whether that’s due to direct action and causing the cancer to grow or whether it’s due to just let’s say allowing the cancer to continue growing, is unknown but it’s probably the latter.

03:22 Side effects of this medication include upper respiratory tract infections.

03:26 About 10% of patients get a URTI when they're on this medication so it’s a particular concern in patients.

03:34 Another thing that we want to be wary about is herpes reactivation.

03:39 We can also see elevated transaminases and we can see increased incidences of urinary tract infections.

03:48 Calcineurin inhibitors are another class of T cell inhibitors.

03:51 Calcineurin activates genes essential for T cell activation and proliferation, such as interleukin 2, IL2.

04:00 Calcineurin inhibitors like tachrolimus and cyclosporine bind to proteins that inhibit calcineurin, blocking T cell activation and proliferation.

04:10 These inhibitors are crucial in preventing organ rejection and treating autoimmune diseases by dampening the immune response.

04:18 B cell inhibitors are a new category of anti-inflammatory agents.

04:22 Rituximab is a very commonly used biologic agent in certain diseases.

04:26 Now this particular drug binds to the CD20 molecule on the surface of the cell.

04:33 What ends up happening is you get reduced calcium influx into B cells and that causes a reduced activity of the B cell.

04:42 Remember the B cell is also an integral part of the immune system just like the T cell, so in a sense, the B cell inhibitors are really a mirror image of the T cell inhibitors.

04:55 You end up having increased destruction of these B cells because of apoptosis or programmed cell death.

05:03 This isn't necessarily a bad thing.

05:05 If you have B cell cancers you can actually treat a B cell cancer potentially with rituximab.

05:13 Medical uses include cancers of white blood system particularly B cell lymphomas and leukemias, and rheumatoid arthritis.

05:22 Rituximab is also used in things like multiple sclerosis, systemic lupus erythematosus, chronic inflammatory demyelinating polyneuropathy, some auto immune diseases.

05:34 You can also use it in pemphigus and pemphigoid, in fact my wife uses, who's a dermatologist, she uses rituximab all the time.

05:42 Finally, it is used in transplant medicine to prevent graph rejection.

05:48 What are the side effects of this particular drug? First of all, infusion reactions.

05:53 I think we all expect that with intravenous or subcutaneous drugs - it’s a very common thing. Cytokine release syndrome and tumor lysis syndrome are two syndromes where when you have wide spread destruction of certain cells you have the intracellular contents being released and they cause different syndromes.

06:11 There's actually a lecture on this in another area of Lecturio so I encourage you to look that up.

06:18 Finally, hepatitis reactivation and of course other viral reactivations can occur when we are using these drug.

06:25 Other potential more serious complications include progressive multifocal leukoencephalopathy due to John Cunningham virus.

06:35 So the JC virus is an interesting phenomenon.

06:38 It wasn't something that we really knew much about but it does cause a leukoencepalopathy in the brain and progressive neurological dysfunction.

06:48 We also worry about immune toxicity with B cell depletion, we worry about pulmonary toxicities as well and finally we worry about bowel obstruction and perforation due to an unknown mechanism.

07:02 Here are several more B-cell inhibitors, all of which are biologics.

07:06 Ocrulizumab targets CD20.

07:08 It is used for multiple sclerosis.

07:10 Ofatamumab, Arzera, binds CD20 more tightly than rituxumab.

07:15 It is used for chronic lymphocytic leukemia.

07:17 Bellumumab is an IgG1 delta monoclonal antibody that inhibits the B-cell activating factor, BAF, preventing its interaction with B-cell receptors.

07:28 B-cell survival and differentiation are reduced.

07:31 It also decreases immunoglobulin production and affects memory B-cell trafficking.

07:36 Then there are inhibitors of both T and B cells.

07:39 These include anti-metabolites, which are drugs that interfere with the normal metabolism of cells, particularly the synthesis of DNA and RNA.

07:49 Mycophenolate mofetil, or cellcept, inhibits an enzyme necessary for the synthesis of guanine nucleotides, which markedly inhibits the proliferation of T and B cells, which rely heavily on this pathway for their growth and function.

08:05 It is used for transplant rejection and lupus nephritis.

08:10 M-TOR inhibitors such as serolimus or rapamycin interfere with T cell proliferation and B cell differentiation.

08:16 It is used to decrease the risk of transplant rejection and to manage some rare diseases.

08:21 Finally, glucocorticoids, such as prednisone, are effective anti-inflammatory agents because they inhibit key signaling pathways in T and B cells, reduce cytokine and immunoglobulin production, and induce cell apoptosis.